A major challenge going forward will be to differentiate the few polymerase variants that reduce replication fidelity and promote cancer from the large number of randomly occurring passenger mutations within POLE and POLD1. Next-generation sequencing of sporadic endometrial and colorectal tumors have made it clear that POLE exonuclease domain mutations (EDMs) are causative in a subset of hypermutated, microsatellite stable (MSS) tumors (reviewed in [99,100]). This evidence concerns the gene POLE and cancer.