N-Myc downstream-regulated gene 4 (NDRG4) is predominantly expressed in the brain as well as in the heart and has been reported to be involved in resistance to neuronal cell death caused by ischemic injury. NDRG4 is a member of the N-Myc downregulated gene family (NDRG) belonging to the alpha/beta hydrolase superfamily. NDRG4 plays an important role in biological processes and pathogenesis. For example, NDRG4 is a tumor suppressor that participates in cell survival, tumor invasion, and angiogenesis. As a novel candidate tumor suppressor, NDRG4 can inhibit PI3K/AKT signal which is related to energy balance and related carcinogenesis. NDRG4 is a candidate tumor suppressor gene in colorectal cancer whose expression is frequently inactivated by promoter methylation. NDRG4 promoter methylation is a potential biomarker for the noninvasive detection of colorectal cancer in stool samples.