Interferon-inducible IFI16 protein (encoded by IFI16 gene located at 1q21 region) is a member of the p200-protein family. The family includes structurally and functionally-related mouse (for example, p202, p203, and p204 proteins) and human (for example, MNDA, AIM2, and IFIX) proteins. Increased expression of p200-family proteins in a variety of cells is known to inhibit cell cycle progression and modulate cell survival. Consistent with this role of p200-family proteins, increased expression of IFI16 protein in normal human diploid fibroblasts and prostate epithelial cells is associated with cellular senescence-associated permanent cell growth arrest. Furthermore, reduced or loss of IFI16 expression in cells is associated with the development of certain cancers, such as breast and prostate cancer. Interestingly, recent studies have provided evidence that the constitutive and interferon-induced expression of the IFI16 gene varies among individuals and may depend on the race. These studies raise the possibility that alterations (increases or decreases) in the expression of IFI16 protein may contribute to the development of human diseases. In this review, we discuss how our understanding of the regulation of IFI16 expression and its role in cell growth regulation will help elucidate the molecular mechanisms that contribute to the development of various human diseases.