May is a great time of year to go to Rome. My wife and I went in 1998 and had a fabulous vacation. Four days to see Rome is just barely enough. You can easily spend three in the city seeing all the sights and then take a day trip to somwhere like Tivoli.
I would disagree with Draginass on making reservations. Pick-up the Lonely Planet guide to Italy in Barnes and Noble or via the Lonely Planet website. It will tell you exactly how to get around town. I recommend taking the train from the airport to Termini and then finding a nice little Pensioni near Termini. That way you are within walking distance of the Coloseum and the major transportation hub. Buses and the Subway are easy to navigate and get around on, walking works well also.
If you arrive off a red-eye flight and get into town early in the morning it is usually easy to walk around Termini and find a decent place with availablity. My wife and I have a set way of doing that. I leave her at the train station with the bags and I go check out the places on foot. That way I can see the rooms and the facilities and then negotiate the price without the owner/manager thinking he has me because I'm tired of lugging a bag around. In Italy we averaged about $45.00 per night for one to three star Pensioni. Rome was the most expensive at over $65.00 for a pretty small but clean room.
If you have more than four days plan on taking the train to wherever you want to go, it is both easier and cheaper than driving or flying. Most of the cities don't allow cars into the cental portion of town or if they do parking is difficult. The train is perfect because the train stations are almost always right in the heart of town and a lot of good Pensioni are nearby. In Venice the exit to the Train station is right on the Grand Canal.
Typical train fares from 1998 were: Rome - Florence one way $23 in second class, Rome - Naples $16 in second class. Florence - Pisa $8.70 round trip. Florence-Venice $20 second class. You get the idea.
I would recommend Florence and Sienna as well as a short afternoon trip to Pisa while in Florence. If you want to go south then Sorrento is a good base of operations for seeing Pompeii, the Amalfi coast, and going out to Capri. If you have longer then three days in Venice is well worth it. I would skip Milan unless your wife is a fashion maven but north of there in the Lakes region is quite nice, especially Lake Como and the real Bellagio.
Have fun,
Typhoonpilot