The genetic instability of cancer cells are due to genetic defects that affect the cell cycle machinery, DNA repair, or cell cycle checkpoints. Examples of the latter two are well known. Since we know a lot about the biochemistry of each of these processes it has been possible to define the genetic changes that lead to loss of fidelity in some cancers and it should be possible in many cancers. These defects should create a vulnerability for the cancer cell relative to the normal cell that could provide a powerful therapeutic advantage if the appropriate vulnerability were targeted for therapeutic intervention.