The threats, both real and perceived, surrounding the development of new and emerging infectious diseases of humans are of critical concern to public health and well-being. Among these risks is the potential for zoonotic transmission to humans of species of the malaria parasite, Plasmodium, that have been considered historically to infect exclusively non-human hosts. Recently observed shifts in the mode, transmission, and presentation of malaria among several species studied are evidenced by shared vectors, atypical symptoms, and novel host-seeking behavior. Collectively, these changes indicate the presence of environmental and ecological pressures that are likely to influence the dynamics of these parasite life cycles and physiological make-up. These may be further affected and amplified by such factors as increased urban development and accelerated rate of climate change. In particular, the extended host-seeking behavior of what were once considered non-human malaria species indicates the specialist niche of human malaria parasites is not a limiting factor that drives the success of blood-borne parasites. While zoonotic transmission of non-human malaria parasites is generally considered to not be possible for the vast majority of Plasmodium species, failure to consider the feasibility of its occurrence may lead to the emergence of a potentially life-threatening blood-borne disease of humans. Here, we argue that recent trends in behavior among what were hitherto considered to be non-human malaria parasites to infect humans call for a cross-disciplinary, ecologically-focused approach to understanding the complexities of the vertebrate host/mosquito vector/malaria parasite triangular relationship. This highlights a pressing need to conduct a multi-species investigation for which we recommend the construction of a database to determine ecological differences among all known Plasmodium species, vectors, and hosts. Closing this knowledge gap may help to inform alternative means of malaria prevention and control.