Substance use disorders (SUD) comprise a broad category of complex phenotypes that constitute a major public health challenge. The etiology of SUD encompasses genetic and environmental components, hampering the identification, validation, replication, and functional assessment of genetic-based therapeutic targets. However, new technological and scientific breakthroughs hold tremendous promise to tease out the underlying genetic and epigenetic signatures associated with SUD, including single nucleotide polymorphisms (SNPs), chromatin interactions, gene expression differences, rare variants, copy number variants, functional SNPs, indels and large chromosomal rearrangements. These technological advances, along with emerging methods to measure environmental exposures and generate human reprogrammed cellular derivatives, have the potential to increase our understanding of the etiology of SUD and accelerate the development of new therapeutic compounds and predictive/diagnostic tests.