Castiglione returned to his home city in the late 1630s, after almost a decade in Rome. Fusing the grandeur of the Roman Baroque with an elegant late Mannerism, he began to establish himself as one of the leading painters in Genoa.

But in 1646, an argument over the valuation of an altarpiece led Castiglione to draw his knife and slash the painting to shreds before the court of the Doge. He fled Genoa and settled back in Rome; four years later he had in turn to flee Rome for Genoa, in such haste that he left all his possessions behind. Though little is known about that episode, he must have felt that his life or his liberty were in immediate danger.

Despite this turbulence, Castiglione remained in favour with powerful patrons: he made the acquaintance of Carlo II Gonzaga, 9th Duke of Mantua, and the godparents to his third child, born in 1648, included Cardinal Lorenzo Raggi and the Marchesa Ortensia Raggi (née Spinola). But his regular removals from one city to another seem to have unsettled Castiglione, and themes of earthly transience became increasingly common in his work.