The mechanosensitive PIEZO family channels, PIEZO1 and PIEZO2, are essential for mechanotransduction and play roles in many cellular processes, including cell volume regulation, tissue development, touch sensation, and proprioception. Emerging evidence suggests roles for PIEZO channels in cancer biology; however, direct mechanistic evidence in breast cancer remains limited. They have been shown to promote proliferation, epithelial-to-mesenchymal transition (EMT), and migration; however, these roles are varied and context-dependent. In breast cancer specifically, the two PIEZO channels may play opposing and complex roles in tumor progression, the tumor microenvironment (TME), and the tumor immune microenvironment (TIME), potentially impacting therapeutic response and prognosis. Where breast cancer-specific mechanistic data are lacking, we integrate findings from other tumor types to generate testable hypotheses relevant to breast cancer. In this review, we will explore the importance of PIEZO channels in breast cancer development, progression, and therapeutic response, and explore therapeutics and potential strategies to improve patient outcomes.