Piero is known to have worked with Veneziano, as his apprentice, on frescoes for the hospital of Santa Maria Nuova in Florence.
Most of Piero's mature work was executed in his hometown of Borgo Santo Sepolcro, or in Arezzo located in Tuscany to the south-east of Florence. His work was neglected for centuries and he was not well regarded in his lifetime. This lack of fame was due to the fact that he never worked in Florence as a mature artist, Piero only worked in Florence as an apprentice and was hardly influenced by Florentine ideas.
In 1442 he was commissioned to paint an altarpiece for the church of the Misericordia in Borgo. He also painted frescoes in the Castello Estense and in the church of Sant'Andrea in Ferrara, but these paintings are sadly lost.
Piero della Francesca also knew Fra Angelico, he was acquainted with Masaccio, Brunelleschi, and the mathematician and architect Alberti.
Piero executed a portrait of Sigismondo Pandolfo Malatesta, the lord of the city-state of Rimini. His work in Rimini included the fresco of Sigismondo Pandolfo Malatesta Praying in Front of St. Sigismund.
The nobleman, Sigismondo Pandolfo Malatesta, was the lord of Rimini from 1432. He was a patron of the arts and had built a reputation as a daring military leader earning him the nickname, The Wolf of Rimini.