Unusual for this period in women's art history, her father was not an artist, but a provincial nobleman in Cremona, who decided to educate his seven children, six daughters and one son, according to the humanist ideals of the Renaissance. Also Sofonisba’s sisters Elena and Lucia Anguissola became painters. 

Surviving works from the 1550s are mostly self-portraits and portraits of her family. Her first dated work is a self-portrait from 1552 when she was twenty years old. This is the first of thirteen self-portraits she documented her life through, the last of which she painted in her late eighties. 

One of her most unusual works, Bernardino Campi Painting Sofonisba Anguissola, offers a new approach in 16th century art. The sitter, her teacher, is engaged in an activity, painting his subject and student Sofonisba. 

Her early works reflected the realistic, descriptive style of the northern Italian artistic tradition. But they also introduced innovations that affected the development of portrait painting. Three of the Artist's Sisters Playing Chess from 1555 has been identified as the first conversation piece, a type of portrait that gained popularity in later centuries, in which the sitter is pictured along with elements of his or her customary surroundings. 

In 1559 Anguissola was invited to Spain to become a court portraitist for Philip II. She returned to Italy around the mid-1570s and lived her remaining years in Genoa, where her fame earned her a respected position. 

Anguissola was a very prolific painter. But her fame as a portrait painter and the demand for her work made it difficult for her to extend her abilities to the other more prestigious categories of painting. 

Her great success inspired other women of the Renaissance to pursue the career of artist. She   became an important role model for artists such as Lavinia Fontana in Bologna and her younger contemporary in Rome, Artemisia Gentileschi. 

In spite of her international acclaim, papal and royal endorsements, and influence of younger male and female artists, history has not been kind to Anguissola. Until only recently, she has been virtually omitted from all major historical accounts of the Renaissance.