Resistance to chemotherapy is a major cause of cancer treatment failure. The acquisition of resistance in cancer is a complex phenomenon that could be driven by tumor heterogeneity and genetic and epigenetic changes. Key processes involved in resistance development during systemic cancer therapy are evolutionary adaptation to therapy, Lamarckian development of resistance induced by treatment and the transfer of resistance factors. These processes can be described through mathematical models that can help in finding optimal ways of treating the tumors deferring or eliminating resistance development.