Built in a 13th-century Romanesque style, with muscular flying buttresses and a striking pink-and-white striped facade, this church is dedicated to St Clare, a spiritual contemporary of St Francis and founder of the Sorelle Povere di Santa Chiara (Order of the Poor Ladies), now known as the Poor Clares. She is buried in the church's crypt, alongside the original Crocifisso di San Damiano, a Byzantine cross before which St Francis was praying when he is said to have received his mission from God in 1205.
The revered cross was moved here from the Chiesa di San Damiano in 1257.