Nucleoside analogs are structurally, metabolically, and pharmacodynamically related agents that nevertheless have diverse biological actions and therapeutic consequences. This class of agents affects the structural integrity of DNA, generally after incorporation during replication or DNA excision repair synthesis, leading to stalled replication forks and chain termination. The DNA damage sensors ATM, ATR and DNA-PK recognize these events. These and other protein kinases activate checkpoint pathways that arrest cell cycle progression, and also signal for DNA repair. In addition, if these survival mechanisms are overwhelmed by the damage caused, a third function of these sensors is to activate signaling pathways that initiate apoptotic processes. A review of the spectrum of responses that are activated by clinically relevant nucleoside analogs begins to provide a mechanistic basis for diverse outcomes in cell viability. Such information, when coupled with an understanding of the intrinsic apoptotic potential of a tumor cell type may provide a rational basis for the design of therapeutic strategies.