It's a varied country, so it really depends on what you want when you are there. I've bene to Rome, Venice, Florence, Garda, Como, Milan, and am off to the North again in the summer. We are probably not going to spend so much time in Milan as I want somewhere a bit chilled, and you can't beat the lakes for that, but if it is your first time you might prefer the history and bustle of Rome or Venice more.
There are flights all over Italy from the UK, and the train network there is really good too.
Vicky