In breast cancer, a protein-folding organelle called the endoplasmic reticulum (ER) can malfunction. This causes misfolded and unfolded proteins to accumulate, causing ER stress and eventually triggering an unfolded protein response (UPR). ER stress and the UPR can contribute to cancer recurrence, metastasis, and drug resistance through different mechanisms in different breast cancer subtypes. Therefore, several drugs have been developed to manipulate UPR pathways in breast cancer. For example, in estrogen receptor– positive breast cancer, the drug ErSO can quickly kill cancer cells by opening estrogen-regulated calcium channels to activate the UPR, while the drug BHP1 can selectively kill endocrine therapy–resistant cancer cells through the PERK UPR pathway. In HER2-positive breast cancer, ATA can similarly activate the PERK pathway to induce cell death while palmitate can activate the IRE1α pathway to reduce anti-HER2 drug resistance. Moreover, in triple-negative breast cancer, the PERK activator TMAO can improve the success of immunotherapy and ilamycin E, which activates CHOP/Bcl-2 UPR signaling, can trigger cell death. However, despite the available drugs, recurrence, metastasis, and resistance remain major challenges emphasizing the need for more research on UPR-targeting therapies in specific breast cancer subtypes.