By train is by far the best option. The high-speed AVE connects Cuenca–Fernando Zóbel station (5 km from the old city) to Madrid Atocha in about 55 minutes. There are around a dozen services daily. This makes Cuenca one of the easiest day trips from Madrid — though it's worth staying overnight to experience the city in the evenings when the day visitors have gone. Trains also connect to Valencia (about 1 hour 20 minutes) and to other Castilian cities via regional services from the old station in the city centre.
By car from Madrid takes around 1 hour 45 minutes via the A-40 motorway. There is a free car park at the edge of the old city (Parking Casco Antiguo), but the lanes of the historic quarter are too narrow for cars. Park at the bottom and walk up.
By bus from Madrid (Estación Sur) takes about 2 hours 15 minutes; there are several services daily operated by Avanza. The bus station is in the new town, about 1 km from the old city centre.
There is no convenient airport: the nearest are Madrid Barajas (180 km) and Valencia (180 km).