He first learned painting from his father Hans Holbein the Elder. Later he went with his brother Ambrosius Holbein to Basel where he met many scholars, among them the Dutch humanist Erasmus. Erasmus asked him to illustrate his satires. Holbein also illustrated other books, including contributing to Martin Luther's translation of the Bible. Like his father, he designed stained-glas windows and painted portraits. The Reformation made it difficult for Holbein to support himself as an artist in Basel and he set out for London. Erasmus furnished him with a letter of introduction addressed to the English statesman and author Sir Thomas More. Holbein painted many portraits at the court of Henry VIII. While there he designed state robes for the king.
In later years he worked in both Basel and London. On one of his stays in London he painted German merchant Georg Giese at the Hanseatic League outpost in London, called the Steelyard (Stalhof).
Holbein painted Anne of Cleves for Henry VIII during marriage negotiations - a common practice in the age before photography. Henry criticized the portrait as having been too flattering. While Holbein was working on another portrait of Henry, he died of plague.
Holbein always made a highly detailed portrait of his subject using pencil, ink and coloured chalk, now considered artpieces in their own right. He transferred the outline of these drawings onto the final painting using tiny holes in the painting through which powdered charcoal was transmitted. In later years, he used a kind of carbon paper. The original drawings were very detailed for the faces, but in general did not include the hands. Clothing was only indicated schematically. The original drawings thus had the same scale as the final paintings.