Leptospirosis is a zoonotic infectious disease of global significance. Political, economic, demographic, ecologic, and other anthropogenically driven environmental changes have fueled the reemergence of this disease in industrialized and developing countries, and in both urban and rural settings. We argue that conventional disciplinary, even interdisciplinary, research methods are not sufficient to elucidate the complex mechanisms and causal relationships among the myriad factors responsible for infectious disease emergence. To address the significant gaps in the field of leptospirosis, an integrated research agenda is needed to guide successful public health remediation of the disease. Based on both working group analysis of literature and newly obtained information, we describe cross-disciplinary collaborative approaches that allow a novel approach to understand leptospirosis emergence with regard to mountain-to-sea ecosystems in Hawai'i and other region-specific ecosystems. Leptospirosis research is a model for how complementary disciplines in the social, cultural, ecological, and biomedical sciences can optimally interact towards a higher understanding of emerging infectious diseases. © 2005 EcoHealth Journal Consortium.