The range of the southern sea otter (Enhydra lutris nereis) spans most of the central California coast from Half Moon Bay to Gaviota. Some coastal areas within this range are heavily developed and highly impacted by humans, while other areas are wild and largely pristine. Determining the relative importance of food resource abundance, environmental conditions, and anthropogenic increases in pathogens and pollutants to population change in sea otters is critical to understanding limitations to population growth. To investigate the causal links between the sluggish population growth of sea otters in central California and factors that could be driving variation in survival and reproduction, we designed a study to compare two distinct subpopulations—one in an area of low human impact (Big Sur) and one in an area of high human impact (Monterey). Between 2008 and 2011, the U.S. Geological Survey and collaborators conducted a telemetry-based study of sea otters at these two locations. The results of this study were not consistent with the hypothesis that sea otters adjacent to human population centers (Monterey) experience higher exposure to pollutants and pathogens than those in lower impacted areas (Big Sur). In fact, based on serological analysis, female sea otters from Big Sur showed higher exposure rates to Toxoplasma gondii than did female otters from Monterey, while domoic acid exposure appeared to be similar at both sites. Gene expression (specifically transcription) analysis did not indicate any consistent differences between the two populations that would have suggested a response to pathogen or toxin exposure, although there were temporal changes in gene transcription for sea otters at Big Sur following potential exposure to run-off from wildfires that occurred during the study. Together, these metrics suggest that variation in exposure to environmental stressors occurred, but patterns were not clearly attributable to differences in human population densities or land-use patterns. When compared to Monterey, sea otters in Big Sur spent more time feeding, had a higher degree of dietary specialization, were in poorer body condition, and had lower survival rates (both pups and adults). Together, these metrics suggest that otters at Big Sur had greater nutritional stress, consistent with lower per-capita resource abundance. Overall, study results indicate that density-dependent population regulation, mediated by per-capita resource abundance, is the most significant factor currently limiting population growth in the center part of the range. Additionally, spatial and temporal variation in environmental and anthropogenic stressors also can affect sea otter health, although patterns of variation are complex and are not simply a function of proximity to human populations. We also found that exposure to environmental stressors (either natural or anthropogenic in origin) often is associated with resource limitation. Finally, our results indicate that sea otter populations are structured at relatively small spatial scales, and the processes that regulate population abundance (including density-dependent resource abundance) also occur at these smaller, more local scales.