In response to environmental stress, cells, like organisms, can respond in two ways: defense by direct resistance against the stressor, or tolerance by increased conformity to the stressor. These strategies have been termed Cellular Life History Programs. The defense program entails protein kinase B (PKB) signaling, aerobic glycolysis, and inflammation, and the tolerance program entails cyclic AMP/protein kinase A (PKA) signaling, catabolism, and oxidative stress resistance. The differentiation of the decidual stromal cell, a uterine cell type unique to placental mammals which functions to support the fetus, occurs in response to the stress of a fetus. We established a model system to differentiate endometrial fibroblasts with signals mimicking pregnancy, the inflammatory mediator prostaglandin E2 and the hormone progestin. Single-cell RNA sequencing revealed that human uterine cells develop through successive stages representing these life history programs: an initial activated defense state transitions into to a pro-tolerance state. This switch is regulated by an evolutionarily derived mechanism, the progesterone-mediated switch to an alternative receptor for prostaglandin E2, subtype 2 (EP2). This receptor specifically activates PKA, helping channel the cell towards tolerance, whereas its paralog EP4 activates PKB. This receptor switch is absent in the opossum, a marsupial, whose endometrial fibroblasts instead mount a failed defense response ultimately leading to cell death. The evolution of pregnancy likely involved elaboration of the pro-tolerance life history program and its embodiment in a specialized cell type. Tolerance of the fetus, long held to be paradoxical, emerged as an elaboration of this ancient cellular program – an active, strategic, and positive form of tolerance – rather than only suppression of defense.