The main road that crosses the Valtiberina in the longitudinal sense is the E45, which connects Cesena to Orte. The connecting exits to reach all the municipalities are those of Sansepolcro and Pieve Santo Stefano.

For those coming from the North, the road to take is the A14 motorway to Cesena and then take the E45, or the A1 motorway to Arezzo. From here follow the signs for Valtiberina-Sansepolcro along the E78 highway.

Those coming from the South can take the E45 to Sansepolcro, or the A1 to Arezzo.

For those coming from Rimini, the State Road 258 - Marecchiese can be a valid alternative to enjoy the beautiful landscapes of the Tuscan-Romagna Apennines.