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 different cancers such as breast (TNBC) and lymphoma (DLBCL), and over-expression of let-7 or miR-34 in cancer cells inhibits their growth, demonstrating a role for these miRNAs as tumor suppressors in human tissue. let-7 and miR-34 regulate the expression of important oncogenes and immune checkpoint genes implicated in multiple cancers, 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 mimics to these 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, including those with a family history of cancer to identify the next generation of cancer biomarkers and targets.