As established in the previous chapters, by the sixteenth century the Ospedale di Santa Maria della Scala was a powerful civic, religious, and economic institution. The rapid growth of the hospital within the city walls as well as the expansion of its patrimony during the thirteenth and fourteenth centuries led to Santa Maria della Scala's position as the dominant charitable institution in the Sienese state. However, as political disagreements and factional divisions split the nobility in the fifteenth and early sixteenth centuries, these troubles were reflected in the hospital's administration and financial stability. The sixteenth century was also a time when Siena, as historian Fausto Landi described it, came into the orbit of the great European powers of France and Spain. Siena's geographical location made it an ideal place to garrison troops, build fortifications, and establish strongholds, and the rich farmland and coastal stretch of the Maremma that Siena controlled made it even more attractive. As the French and Spanish monarchs battled over the Italian peninsula, both were eager to gain a hold over Siena. Closer to home, Siena's neighbouring enemy Florence sought to expand its territory, with Cosimo I de’ Medici's end goal being Florentine control of Tuscany. The mixture of outside forces with Siena's internal divisions created a volatile political environment and a competition for power which erupted into war in 1552.

As the owner of one-third of the land which comprised the Sienese state and its dominant charitable institution, Santa Maria della Scala was deeply involved in and affected by these disputes. The bonds forged between city and countryside became especially crucial during the war. As Mario Ascheri argued, the participation and support of Siena's contado during the war emphasized the profound fidelity between urban and rural spaces that was the foundation of Sienese civilization. The hospitals and farms of Santa Maria della Scala were a key part of this relationship and played a crucial role in the stability and survival of the hospital as well as Siena's broader community throughout this crisis. Additionally, the hospital's experience provides valuable perspective on the ways in which the war affected Sienese society. Most sources treat the war of Siena from a political point of view, examining it in terms of the end of the Republic of Siena, the growth of the Tuscan state, or the power struggle between France and Spain over Italy.