A recent publication by Bornes and colleagues explored the impact of the estrous cycle on mammary tumor response to neoadjuvant chemotherapy. Using genetically engineered mouse models, Bornes and colleagues revealed that chemotherapy is less effective when initiated during the diestrous stage compared with during the estrous stage. A number of changes during diestrus were identified that may reduce chemosensitivity of mammary tumors: an increased mesenchymal state of breast cancer cells during diestrus, decreased blood vessel diameters, and higher numbers of macrophages in the tumor microenvironment. Macrophage depletion was sufficient to mitigate this resistance. To translate these findings to humans, retrospective analyses of premenopausal patients with breast cancer were conducted. Serum progesterone levels served to determine the menstrual cycle phases, which revealed that treatment efficacy is reduced in women receiving neoadjuvant chemotherapy during the luteal (progesterone-high) phase compared with those treated during the follicular (progesterone-low) phase. The findings show that physiologic hormone fluctuations may influence chemosensitivity through tumor cell-extrinsic mechanisms, with the important implication that aligning treatment initiation with the menstrual cycle improves therapeutic outcomes and that consideration of systemic factors may improve therapy outcomes.