MicroRNAs are small non-coding RNAs that regulate gene expression to control important aspects of development and metabolism such as cell differentiation, apoptosis and lifespan. miR-21, miR-155, let-7 and miR-34 are microRNAs implicated in human cancer. Specifically, human let-7 and miR-34 are poorly expressed or deleted in lung cancer, and over-expression of let-7 or miR-34 in lung cancer cells inhibits their growth, demonstrating a role for these miRNAs as tumor suppressors in lung tissue. let-7 and miR-34 regulate the expression of important oncogenes implicated in lung cancer, suggesting a mechanism for their involvement in cancer. We are focused on the role of these genes in regulating proto-oncogene expression during development and cancer, and on using miRNAs to suppress tumorigenesis. In contrast, miR-21 and miR-155 are oncomiRs and up-regulated in many cancer types. We are also developing effective strategies to target these miRNAs as a novel anti-cancer approach. Lastly we are examining the non-coding portions of the genome for mutations and variants that are likely to impact the cancer phenotype. We have successfully resequenced the 3’UTRome and microRNAome from cancer patients with a family history of cancer.