•A review of the DNA double strand break repair pathway non-homologous end-joining is provided.•The important proteins and mechanisms modulating non-homologous end-joining are highlighted.•Emphasis is given to the DNA-PK complex and the versatility of non-homologous end-joining for the repair of DNA double-stranded breaks. DNA double stranded breaks (DSBs) are the most cytoxic DNA lesion as the inability to properly repair them can lead to genomic instability and tumorigenesis. The prominent DSB repair pathway in humans is non-homologous end-joining (NHEJ). In the simplest sense, NHEJ mediates the direct re-ligation of the broken DNA molecule. However, NHEJ is a complex and versatile process that can repair DSBs with a variety of damages and ends via the utilization of a significant number of proteins. In this review we will describe the important factors and mechanisms modulating NHEJ with emphasis given to the versatility of this repair process and the DNA-PK complex.