Preclinical models of cancer have demonstrated enhanced efficacy of cell-cycle checkpoint kinase inhibitors when used in combination with genotoxic agents. This combination therapy is predicted to be exquisitely toxic to cells with a deficient G1-S checkpoint or cells with a genetic predisposition leading to intrinsic DNA replication stress, as these cancer cells become fully dependent on the intra-S and G2-M checkpoints for DNA repair and cellular survival. Therefore, abolishing remaining cell-cycle checkpoints after damage leads to increased cell death in a tumor cell-specific fashion. However, the preclinical success of these drug combinations is not consistently replicated in clinical trials. Here, we provide a perspective on the translation of preclinical studies into rationally designed clinical studies. We will discuss successes and failures of current treatment combinations and drug regimens and provide a detailed overview of all clinical trials using ATR, CHK1, or WEE1 inhibitors in combination with genotoxic agents. This highlights the need for revised patient stratification and the use of appropriate pharmacodynamic biomarkers to improve the success rate of clinical trials.