In deep sea hydrothermal vent environments, metal- and metalloid-enriched fluids and sediments abound, making these habitats ideal to study metal resistance in prokaryotes. In this investigation, the architecture of the Epsilonproteobacterium, Nitratiruptor sp. SB155-2 transcriptome in combination with sub-cellular analysis using scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy (STEM-EDX) was examined to better understand mechanisms of tolerance for cadmium (Cd) and copper (Cu) at stress-inducing concentrations. Transcriptomic expression profiles were remarkably different in the presence of these two metals, displaying 385 (19%) and 629 (31%) genes differentially expressed (DE) in the presence of Cd and Cu, respectively, while only 7% of DE genes were shared, with genes for non-specific metal transporters and genes involved in oxidative stress-response predominating. The principal metal-specific DE pathways under Cu stress, including those involving sulfur, cysteine, and methionine, are likely required for high-affinity efflux systems, while stress and flagella formation and chemotaxis were over-represented under Cd stress. Consistent with these differences, STEM-EDX analysis revealed that polyphosphate-like granules (pPLG), the formation of Cd-S particles, and the periplasmic space may be crucial for Cd sequestration. Overall, this study provides new insights regarding metal-specific adaptations of Epsilonproteobacteria to deep sea hydrothermal vent environments.