Cancer development involves multiple genetic changes, which can occur in tumor suppressor genes and lead to loss of function in a recessive manner. Recent findings have identified a novel tumor suppressor gene named GRIM-19. Similar to what has been observed for other known tumor suppressor proteins such as p53, GRIM-19 gene mutations and loss of protein expression have been observed in several tumor types. In this review, we perform a detailed description on the current understanding of GRIM-19 function in carcinogenesis.