The order Sirenia is represented by three species of manatees and one species of dugong distributed in tropical and subtropical regions of the world and considered vulnerable to extinction. The sentinel species concept is useful to identify indicators of the environment and may reflect the quality of health in marine ecosystems. The single species approach to evaluate ecological health may provide a series of “snap shots” of environmental changes to determine if animal, human, or ecosystem health may be affected. Under this concept, marine vertebrates may be good integrators of changes over space and time, and excellent sentinels of ecosystem health. Based on their life history, manatees may or may not be ideal sentinels, as they are robust, long-lived species and appear remarkably resilient to natural disease and the effects of human-related injury and trauma. These characteristics might be the result of an efficient and responsive immune system compared to other marine mammals. Although relatively immune to infectious agents, manatees face other potentially serious threats, including epizootic diseases and pollution while in large aggregations. Manatees can serve as excellent sentinels of harmful algal blooms due to their high sensitivity, specifically to brevetoxicosis, which has caused at least two major die-offs in recent times. Threats to manatees worldwide, such as illegal hunting and boat collisions, are increasing. Habitat is being lost at an alarming rate and the full effects of uncontrolled human population growth on the species are unknown. The manatee may serve as a sentinel species, prognosticating the deleterious effects of unhealthy marine and aquatic ecosystems on humans. We have identified a number of critical research needs and opportunities for transdisciplinary collaboration that could help advance the use of the sentinel species concept in marine ecosystem health and monitoring of disease emergence using our knowledge on these magnificent sirenians.