In May I fly to Florence IT from the US, changing planes (airlines) in Frankfurt DE. How much time should I best allow to enable me to "safely" make the second flight, given the size and operations of the airport?
Minimum Connection Time in Frankfurt is 45 minutes, so 45 minutes is a legal - and normally doable connection, however to be on the safe side you should maybe allow a little more, maybe 1h15 minutes or so. I must say though, that I once had a 45 minutes connection in Frankfurt from a intra Europe flight to a long haul flight. The connection time was even reduced to 35 minutes since my incoming flight was late, but I made it without any problems!
We made an hour connection there last summer, but barely. We had to go through 2 security checkpoints, but I'm not sure what you'll have to go through, security-wise, coming from Florence.