Itinerary help - first time to Italy

With so many variables at play, I suggest starting with flight searches--out of both departure points, and all open-jaw combinations including Venice, Florence, Pisa, and Milan. I would shoot for the happy medium of October, but I think any month would be fine, though I'd worry a bit more about inclement weather the later you go.
It is often the case that departures out of Venice leave at an ungodly hour, so people often suggest starting there.
Just sorting out the travel will help get you focused, and in the meantime you might look over books to narrow down where in the lakes and Tuscany. You will only need a car for rural Tuscany.

Even two nights in Venice would be insufficient for me, all the more so if it turns out to be your first stop, since Day 1 is often experienced in a sleep-deprived, jetlagged haze. The problem with quick stops in Venice is that you end up just hitting the highlights--the same places all the other visitors go--and are constantly surrounded by teeming crowds. If you allow yourself more time, you'll be able to wander off the beaten path, and you'll probably love Venice. With just one or two nights, you may be among those who say they were glad they didn't stay longer.

I agree that it makes sense to start by looking at airfares. I suspect you'll save money by flying out of Boston vs. Richmond, perhaps a substantial amount. From Washington DC Milan and Rome are usually the cheapest Italian destinations. It might be different from Norfolk and Boston. Distances in northern Italy are short enough, and rail fares cheap enough, that if you need to simply fly round-trip into (for example) Milan, it won't cost you a lot of extra time. Remember, though, that you'll want to spend your last night not too far from your departure point.

Tuscany, Florence, Venice and Lake Como. We want to spend a smaller amount of time in Venice (1-2 nights) and then 3-4 nights in all the other spots depending on how it falls.

2 nights Venice + 3 nights in each of 3 other places = 11. One night in Venice makes no sense at all, and as acraven said, 2 is really insufficient. Make Venice 3 nights and select two other stops. You can easily spend 5 nights in Florence or Cortona and day trip around Tuscany. If you select Cortona, you should rent a car, but you can take a train to Florence (Firenze) for a day. As I do not see art in your list of desired experiences, a day will give you a nice taste and you can see if you might want to go there another time. Staying 5 nights somewhere like this -- whether Cortona or Firenze -- would make for a pleasant pace and less go-go-go.

The other 3 nights could be spent carless in Varenna on Lake Como. However, Varenna is probably only a viable destination up until mid-October at the latest. If you go later, I'd select another stop. The lakeside and seaside locations in Italy are not great destinations off-season.

I'd agree that you might want to start with flights. In my experience, flying out of JFK to Venice/Florence is considerably more $$ than to Milan or Rome. Where you fly into will guide your itinerary.

I'm a "go go go" kind of traveler, and I can't imagine how I'd enjoy Venice staying only one night. The places you'd want to see are on the other end of the Grand Canal from where the train station is. An amazing city, but not very convenient in terms of getting to places quickly, esp with luggage. The streets are tiny and windy, you're guaranteed to get lost, there are millions of bridges and the canal to cross... If you stay closer to the train station, you'll be far from most things to see on San Marco (also where boats depart for Murano & Burano). If you stay closer to San Marco, you'll be dragging luggage on the canal on back to to back days. The best part of Venice, IMHO, is simply getting lost, wondering around seeing where that seemingly dead end street takes you. I would def leave one full day for that w/o worrying about making it back on time to make your connection. Even 2 nights are prob not enough.

If anything, Florence could be a place to cut - the touristy things (I'm guessing you'd want to see David, Uffiza, Ponte Vecchio since it's your first time) are close to each other and you can pre-book. I'm not suggesting Florence is not worth the time, but I found it easier to do more in a day w/proper planning. Florence is so hectic you'll likely be in "go go" mode even if you're just sitting around, so I'd just accept that I wont relax much and go see as much as possible, then rest from it all in Tuscany.

If renting a car, I'd confirm 10 times :) that it's automatic (unless you're good w/manual). In Florence I got a manual after reserving an automatic. The only automatic they had was a BMW 7-series. Same thing happened in Paris too. Luckily I can drive manual, so they didn't cash in as they prob hoped. If it sounds too good to be true (your rental rate is $30/day for an automatic)...it probably is.

4 destinations in 11 days is gogogo in my book. cut out one to enjoy the other 3. Reread your heading: first time to Italy. If you try to pack in too much, you'll only cheat yourselves in the long run. Less is more.

I'll agree that Venice needs 3 nights, especially if it's your arrival city, and then choose just 2 more locations. What those may be - as in the case of Cortona - depends on your willingness to drive: fine for some folks but not something everyone is comfortable getting behind the wheel the first time on foreign territory, and Italy involves some homework there. Still, quite a number of folks do OK puttering around non-urban Tuscany by car. It does put a damper on a plan to do more than the merest of wine tastings, though.

Florence is a good base for a number of day trips via public transport (you don't want a car if staying here) - although not really to wineries - so is a nice choice for first-timers getting their feet wet in Italy.

As previously mentioned, you don't need a car in Varenna as you can get around by ferry if you go before the off season.

Whatever you choose, you'll want to be close to your airport of departure the night before, and I'd try to fly open-jaw (into one city and out of another) to avoid backtracking.

Meg, with "...views, food, wineries, sightseeing...bit of history...relaxed time...less go go go" being your main focus, consider the following. Fly into Milan and head straight to Lake Como. Wonderful place to relax, unwind, and recover from any jet lag. After a couple or three days take the train to Venice for another three or four days. Finish up in Florence and fly back from there. It is astounding the amount of time you will "lose" just relocating from one place to another. Your trip sounds like one where less is more.