The DNA-dependent protein kinase (DNA-PK) is central to the process of nonhomologous end joining because it recognizes and then binds double strand breaks initiating repair. It has long been appreciated that DNA-PK protects DNA ends to promote end joining. Here we review recent work from our laboratories and others demonstrating that DNA-PK can regulate end access both positively and negatively. This is accomplished via distinct autophosphorylation events that result in opposing effects on DNA end access. Additional autophosphorylations that are both physically and functionally distinct serve to regulate kinase activity and complex dissociation. Finally, DNA-PK both positively and negatively regulates DNA end access to repair via the homologous recombination pathway. This has particularly important implications in human cells because of DNA-PK's cellular abundance.