In this chapter we introduce proteins controlling transition through the cell division cycle, with particular focus on the controllers of mitosis, and we describe their role in the development of cancer. The essay begins with a historical perspective on the discoveries that led to the formulation of "The Cell Theory" and the understanding of mechanisms controlling cell cycle transitions. This is followed by an in-depth description of pathways that monitor the appropriate completion of events in each phase of the cell division cycle (the checkpoints) and an analysis of the many dysfunctions that alter these mechanisms and account for the occurrence of cancer. The essay is concluded by some considerations on the opportunity of putting effort, both in basic research and drug discovery programs, on the full clarification of the G2/M checkpoint, which is the only checkpoint that tumors in the body and experimental systems have in common. The rationale to this suggestion is that combinations of low-dose radio- or chemotherapy and selective G2/M checkpoint inhibitors will be more effective in achieving tumor clearance than current conventional protocols.