Drug resistance is one of the main causes of chemotherapy failure. Although several factors are involved in cancer drug resistant, the exporter pumps overexpression that mediates the drugs flow to outside the cells and reduces both the drugs intracellular concentration and effectiveness, has been one of the most important challenges. Overexpression of ABCC3, a member of the ABCC subfamily, has been strongly associated to the resistance to multiple drugs. ABCC3 has been found highly expressed in different types of cancers and is associated with poor prognosis and resistance to treatments. In this review, we summarize the molecular mechanisms involved in cancer drug resistance and discuss the current knowledge about the structure, function and role of ABCC3 in drug resistance, as well as, the expression status of ABCC3 in different types of cancer. We also provide evidences that place ABCC3 as a potential therapeutic target for improving the cancer treatment by focusing on the need of developing more effective cancer therapies to target ABCC3 in translational researches.