Chromosomal abnormalities at the 3p21.3 region, including homozygous deletions and loss of heterozygosity and expressional deficiencies in 3p21.3 genes including transcriptional silences by promoter hypermethylation, altered mRNA splicing and aberrant transcripts, and lost or defect protein translation and post-translational modifications, are frequently found in most human cancers. Inactivation of 3p21.3 genes in primary tumors affects a wide spectrum of key biological processes such as cell proliferation, cell cycle kinetics, signaling transduction, ion exchange and transportation, apoptosis and cell death, and demonstrates the molecular signatures of carcinogenesis. Restoration of defective 3p21.3 genes with several wild-type 3p21.3 genes suppresses tumor cell growth both in vitro and in vivo. These findings suggest several 3p21.3 genes as potential tumor suppressors and implicates these 3p21.3 genes for future development as biomarkers for the early detection and diagnosis of cancer, and as prognostic and therapeutic tools for cancer prevention and molecular cancer therapy.