In addition to innate and gained resistance poliploidy of cancer cells is described as a mechanism responsible for lack of response or cancer relapses after initial patient recovery. Formation of these cells is induced by cyto- and genotoxic agents, which trigger endoreduplication, cytokinesis failure, cell fusion or canibalism. These processes lead to amplification of DNA, cell cycle arrest and escape from death. Cancer reinitiation results from depolyploidization by neosis, amitotic and meiotic-like divisions. In this paper we review the known mechanisms, which drive cancer cell transition to poliploidy, major features of these cells and their role in cancer progression. We also depict the current approaches, which target metabolic and signaling pathways that are crucial for survival and functioning of polyploid cells. The combination of chemotherapy and radiotherapy with agents capable of inhibiting or eliminating polyploid cells could substantially improve the success rate and efficacy of anticancer therapies.