The deep ocean is one of the largest and least studied biomes on Earth. The microbes inhabiting these locales require physiological adaptations to handle the associated extreme environmental conditions, including high hydrostatic pressure, low temperatures, and low organic carbon. Few microbes have been successfully cultured that are capable of growth under in situ high-pressure conditions, especially at hadal depths, thanks to the relative inaccessibility of these sites, an inability to collect samples and maintain them under in situ conditions, and difficulties in culturing methodology. However, genome sequencing and high-throughput community analyses have provided insight into the prokaryotes which inhabit the deep sea and their lifestyles. This review discusses our current understanding of microbial adaptation to the deep-ocean through genomic comparisons of deep-ocean adapted microbial ecotypes and their shallow-water counterparts, including opportunistic heterotrophic microbes belonging to the Gammaproteobacteria and the fastidious taxa SAR11 and Thaumarchaea. These comparisons are addressed in the context of culture-independent metagenomics and community diversity analyses on deep, oligotrophic pelagic communities. Both culture-dependent and—independent analyses suggest the presence of bathytypes as both isolates and whole communities are distinct from those found above them. While these studies show many attributes indicative of deep-ocean genomes, including genes for particle-association, heavy-metal resistance, the loss of a UV photolyase, and increased abundances of mobile elements, they also suggest that high-pressure adaptation seems to arise from the accumulation of many small changes, such as differences in gene expression or the accumulation of compatible solutes. Genomic analyses on a larger dataset of samples and piezophilic isolates are necessary to distinguish attributes specific to deep-sea adaptation.