Piero's father, a goldsmith named Lorenzo, recognised his son's lively intelligence and inclination toward design and placed him with Cosimo Rosselli, who took him on with unusual willingness and, as his ability grew alongside his years, came to love him as a son^[1]. Vasari records that Rosselli made such use of his pupil's talent that he often entrusted him with work of real importance, judging that Piero had a finer manner and better judgement than Rosselli's own^[1]. When Rosselli was summoned to Rome by Pope Sixtus IV to paint scenes for his chapel, he brought Piero with him, and it was Piero who painted a landscape in one of those scenes considered among the finest work in the whole chapel^[1].

Piero absorbed the coloured oil technique of Leonardo da Vinci once Leonardo had returned to Florence, taken by the gradation of colour and the extraordinary diligence Leonardo brought to his finished work^[1]. But Piero moved his own style well away from Leonardo's example, and indeed away from any single fixed manner at all; Vasari records that Piero seemed to change his approach with almost every picture he painted^[1]. That restlessness extended to subject matter as much as technique. Piero filled his mythological and fantastical scenes with invented architecture, strange creatures and fantastic costumes rather than the more ordered, conventional compositions favoured by his Florentine contemporaries, and he described finding inspiration by staring at old walls marked with stains until he could picture entire battles of horsemen and vast imagined cities within the marks^[1].

After the death of his master Cosimo Rosselli, Piero withdrew increasingly from ordinary life, according to Vasari, keeping himself shut away and refusing to let others watch him work, living, in Vasari's description, more like a beast than a man^[1]. He would not permit his rooms to be swept, ate only when hunger struck him, and let his garden run entirely wild, his vines trailing untended and his fruit trees left unpruned, believing that nature's own things should be left to nature's own care^[1]. Later historians have treated this account with some caution, noting that Vasari applied similar language of eccentricity and beast-like withdrawal to several artists across his Lives, including Piero, whom he twice calls bestial, a term he also used for the spendthrift Botticelli, so the portrait may owe something to a recurring literary type in Vasari's writing as well as to Piero's genuine character^[2][3].