A vigorous effort to identify and study sentinel species of marine ecosystem in the world’s oceans has developed over the past 50 years. The One Health concept recognizes that the health of humans is connected to the health of animals and the environment. Species ranging from invertebrate to large marine vertebrates have acted as “sentinels” of the exposure to environmental stressors and health impacts on the environment that may also affect human health. Sentinel species can signal warnings, at different levels, about the potential impacts on a specific ecosystem. These warnings can help manage the abiotic and anthropogenic stressors (e.g., climate change, chemical and microbial pollutants, marine litter) affecting ecosystems, biota, and human health. The effects of exposure to multiple stressors, including pollutants, in the marine environment may be seen at multiple trophic levels of the ecosystem. Attention has focused on the large marine vertebrates, for several reasons. In the past, the use of large marine vertebrates in monitoring and assessing the marine ecosystem has been criticized. The fact that these species are pelagic and highly mobile has led to the suggestion that they are not useful indicators or sentinel species. In recent years, however, an alternative view has emerged: when we have a sufficient understanding of differences in species distribution and behavior in space and time, these species can be extremely valuable sentinels of environmental quality. Knowledge of the status of large vertebrate populations is crucial for understanding the health of the ecosystem and instigating mitigation measures for the conservation of large vertebrates. For example, it is well known that the various cetacean species exhibit different home ranges and occupy different habitats. This knowledge can be used in “hot spot” areas, such as the Mediterranean Basin, where different species can serve as sentinels of marine environmental quality. Organisms that have relatively long life spans (such as cetaceans) allow for the study of chronic diseases, including reproductive alterations, abnormalities in growth and development, and cancer. As apex predators, marine mammals feed at or near the top of the food chain. As the result of biomagnification, the levels of anthropogenic contaminants found in the tissues of top predators and long-living species are typically high. Finally, the application of consistent examination procedures and biochemical, immunological, and microbiological techniques, combined with pathological examination and behavioral analysis, has led to the development of health assessment methods at the individual and population levels in wild marine mammals. With these tools in hand, investigators have begun to explore and understand the relationships between exposures to environmental stressors and a range of disease end points in sentinel species (ranging from invertebrates to marine mammals) as an indicator of ecosystem health and a harbinger of human health and well-being.