Much speculation exists on the exact circumstances under which Marie de' Medici decided to commission Rubens to paint "such a grandiose project, conceived in truly heroic proportions". John Coolidge suggests the cycle may have even been commissioned to rival another famous series of Rubens, The Constantine Tapestries, which he designed in his studio at the same time as the first several paintings of the Medici Cycle. It has also been suggested that Rubens prepared a number of oil sketches, by the request of Louis XIII, the son of Marie de’ Medici and successor to the throne, which may have influenced the Queen's decision to commission Rubens for the cycle by the end of the year 1621. The immortalizing of her life, however, seems to be the most apparent reason for the Queen's choice to commission a painter who was capable of executing such a demanding task. Peter Paul Rubens had already established himself as an exceptional painter and also had the advantage of sustaining close ties with several important people of the time, including Marie de' Medici's sister, the wife of one of Rubens's first important patrons, the Duke of Gonzaga. The information about the commission in the contract Rubens signed is far from detailed and focuses mainly on the number of pictures in the cycle dedicated to the Queen's life, and is far less specific when it comes to the cycle praising her husband Henry IV. The contract stated that Rubens was to paint all the figures, which presumably allowed him to employ assistants for backgrounds and details.
Marie de' Medici became the second wife to King Henry IV of France in a marriage by proxy on 5 October 1600 by the power invested in her uncle, Grand Duke Ferdinand of Tuscany. When Henry was assassinated in 1610, Louis XIII, his son and successor to the throne, was only eight years old. Louis' mother, Marie, acted as his regent as commanded by the Frankish Salic law in case of an infant ruler. However, even after Louis came of age at thirteen in 1614, the queen continued ruling in his stead. In 1617, Louis XIII finally decided to take governing matters in his own hands at the age of fifteen and the queen was exiled to Blois.
Louis and his mother were not reconciled for over four years, and finally in 1621 Marie was permitted to return to Paris. Upon her return, Marie focused on building and decorating the Luxembourg Palace, an enormous undertaking in which Peter Paul Rubens played a key role. Rubens, then court painter to the Duchy of Mantua under Vincenzo I Gonzaga, had first met Marie at her proxy wedding in Florence in 1600. In 1621, Marie de' Medici commissioned Rubens to paint two large series depicting the lives of herself and her late husband, Henry IV, to adorn both wings of the first floor of the Luxembourg Palace. The first series of 21 canvases depicts the life of Marie in largely allegorical terms, and was finished by the end of 1624, to coincide with the celebrations surrounding the wedding of her daughter, Henrietta Maria to Charles I of England on 11 May 1625. The cycle of paintings dedicated to the life of Henry IV was never completed, although some preliminary sketches survive. (See #Henry IV Cycle below). The fact that the Henry IV series was not realized can be attributed in part to Marie de' Medici being permanently banned from France by her son in 1631. She escaped to Brussels, and later died in exile in 1642 in the same house that the Peter Paul Rubens's family had occupied more than fifty years prior.
While this cycle was one of Rubens's first great commissions, Marie de' Medici's life proved a difficult one to portray. Rubens had the task of creating twenty-one paintings about a woman whose life could be measured by her marriage to Henry IV and the births of her six children, one of which died in infancy. At this time, women did not in general receive such laudatory tributes, although Rubens, if anyone, was well equipped for the job, having a great respect for "the virtues of the opposite sex", as seen in his commissions for the Archduchess Isabella. Furthermore, unlike her husband, Marie's life was neither graced with triumphant victories nor punctuated by vanquished foes. Rather, implications of political scandal in her life made any literal depiction of the events far too controversial for Rubens to execute without incurring the disapproval from others in government. Far from failing, Rubens demonstrated his impressive knowledge of classical literature and artistic traditions, by using allegorical representations to both glorify the mundane aspects and sensitively illustrate the less favorable events in Marie's life. During the sixteenth and seventeenth centuries iconography of the Christian world, as well as that of the Greek and Roman pantheon was understood by well-educated artists and citizens alike, and a familiar device used in artistry. Rubens painted extravagant images of the Queen Mother surrounded by ancient gods and at times even deified her using these devices. The ambiguity of the figures was essentially used to depict Marie in a positive light.
Rubens's Medici commission was an inspiration for other artists as well, particularly the French painters Jean-Antoine Watteau (1684–1721) and François Boucher (1703–1770) who produced copies from the Medici cycle.