In this review, we will explore and seek to reconcile this paradox by presenting a comprehensive overview of the literature examining the role that the core NHEJ factors, Ku70 (XRCC6), Ku80 (XRCC5), DNA-PKcs (PRKDC or XRCC7), LIG4 (LIG4), XRCC4 (XRCC4), and XLF (NHEJ1), play in protecting the genome and how dysregulation of these factors influences carcinogenesis, cancer progression and aggressiveness, and patient survival. Here, LIG4 is linked to cancer.