Cancer is a complex category of diseases caused in large part by genetic or genomic, transcriptomic, and epigenetic or epigenomic alterations in affected cells and the surrounding microenvironment. Carcinogenesis reflects the clonal expansion of cells that progressively acquire these genetic and epigenetic alterations-changes that, in turn, lead to modifications at the RNA level. Gradually advancing technology and most recently, the advent of next-generation sequencing (NGS), combined with bioinformatics analytic tools, have revolutionized our ability to interrogate cancer cells. The ultimate goal is to apply these high-throughput technologies to the various aspects of clinical cancer care: cancer-risk assessment, diagnosis, as well as target identification for treatment and prevention. In this article, we emphasize how the knowledge gained through large-scale omics-oriented approaches, with a focus on variations at the level of nucleic acids, can inform the field of chemoprevention.