Key West International Airport (EYW) has direct flights from several US hubs, though fares run high — many visitors fly into Miami or Fort Lauderdale and drive the 3.5-4 hour Overseas Highway (US-1) instead, one of the great American road trips.
Once in town, Old Town is entirely walkable or bikeable — a car is a liability given limited/expensive parking. Bike and scooter rentals are everywhere; the free Duval Loop trolley and the paid Conch Tour Train cover the rest.