It is widely recognized that the evasion of apoptotic cell death is one of the hallmarks of cancer. For many years cytotoxic agents have been developed to target apoptotic cell death as a main method of treating cancer. However, the occurrence of cellular defects involving the apoptotic machinery in many cancers has resulted in an acquired resistance to apoptotic cell death, undermining the effectiveness of chemotherapeutic agents. Over the past decade, research has revealed a growing number of cell death pathways that are not dependent on apoptosis. In addition, compounds specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. These novel anticancer agents are critically discussed by the authors, and therefore, the current Perspective represents a resource for a practicing medicinal chemist looking for new opportunities to combat cancers resistant to the established proapoptotic therapeutic agents.