Acquisition of resistance to the cytotoxic effects of anticancer agents is one of the most significant impediments to effective cancer therapy. Although various cancer-cell intrinsic mechanisms of drug resistance have been identified, chemotherapy resistance remains one of the major causes of cancer patient death. Emerging evidence suggests that the inflammatory tumor-microenvironment plays an important additional role in modulating drug responsiveness and drug resistance; however, underlying mechanisms are still largely unknown. In this review, we discuss data supporting the idea that crosstalk between components of the immune system and cancer cells can influence chemoresistance, and we will speculate on possible underlying pathways and clinical implications. A deeper understanding of the cancer cell-intrinsic and -extrinsic mechanisms of drug resistance will accelerate the development of novel combinatorial anticancer therapies in which drug resistance is prevented or reversed.