Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members SMAD4. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. SMAD4 R361C lies at a hotspot residue within MH2 domain and has displayed reduced SMAD4 transactivating activity in cell assays. Somatic SMAD4 mutations have been reported to be more common in advanced stages of CRCs. Studies of loss of function somatic mutations and studies of loss of heterozygosity (LOH) at the SMAD4 locus have shown an association with poor prognosis. SMAD4 mutations were also associated with mucinous histology. There are ongoing clinical trials for colorectal tumors harboring SMAD4 alterations.