Chemotherapy resistance is an important problem often encountered during the course of breast cancer treatment. In order to design rational and efficacious therapies, the molecular mechanisms used by cells to develop resistance must be investigated. One mechanism employed by cancer cells is to alter cell signaling. This review examines the role of mitogen-activated protein kinases (MAPKs) and their endogenous negative regulators, mitogen-activated protein kinase phosphatases (MKPs), in chemotherapy resistance in breast cancer. MAPK signaling is activated in response to both growth factors and cellular stress. MKPs dephosphorylate MAPKs and are part of the dual-specificity family of phosphatases. MAPKs have been shown to be involved in resistance to tamoxifen, and MKPs have been linked to resistance to treatment with doxorubicin, mechlorethamine, paclitaxel, proteasome inhibitors, and oxidative-stress-induced cell death in breast cancer. The role of MKPs in tamoxifen resistance and the elucidation of the mechanisms involved with resistance to standard chemotherapy agents need to be investigated further. Growing evidence suggests that modulating MKP-1 activity could be a viable option to make breast cancer chemotherapy more effective.