Some of the greatest human health impacts from climate change are mediated by infectious diseases. Billions are at risk annually from malaria alone, and viral pathogen spillover events and spread of vector-borne diseases (VBD) are increasing due to climate change. In response to these urgent threats, Cornell University and the University of Pretoria have newly partnered to create the Center for Transformative Infectious Disease Research on Climate, Health and Equity in a Changing Environment (C-CHANGE). To have the greatest health impacts, we must change research and practice paradigms from reactive focus on response to outbreaks to proactive understanding of the complex social and environmental determinants that promote risk of outbreaks. We hypothesize that community-engaged research integrating human, reservoir and vector behavior, climate, land-use, human and animal health, and vector/pathogen genomic evolution datasets, will enable creation of predictive epidemiological models and future generation and rigorous testing of preventative interventions. Improved understanding of these relationships will also facilitate current preparation/response. Working toward these goals, we integrate dimensions of building research capacity and performing transdisciplinary research in every element of C-CHANGE. Administrative Core (Travis, Oosthuizen, co-PIs): will facilitate routine meetings; administer a pilot grant competition with preference for Early Stage Investigators (ESI) to generate preliminary data and test feasibility for future studies; and organize transdisciplinary training for ESIs, post-doctoral and graduate student trainees to broaden their skills and network for future climate change and health research. Living Evidence Applied Data Modeling Core (Hayden-ESI; Smith-ESI; Marivate-ESI, co-leads): will federate current datasets from 4 continents and provide transdisciplinary modeling expertise to enable researchers to integrate climate, land-use, animal and human health, and genomic data to help identify generalizable vs context-specific relationships. Community Engagement Core (Meredith-ESI, van Wyk, co-leads): will engage with every project to enable/perform community-informed research that is relevant and can effect long-term positive change, and will perform comparative surveys in South Africa, Zimbabwe and the US to lay foundations for future research proposals. Project 1 (Plowright, Markotter, co-leads): hypothesizes that climate extremes and land use changes result in wildlife stress, increasing both viral shedding and interaction with humans, facilitating viral spillover events (paramyxo-, corona-, and filoviruses). Project 2 (Goodman-ESI, de Jager, Riddin-ESI, Ueckermann-ESI, Oosthuizen, co-leads): hypothesizes that an integrated framework for a community-based early warning system for climate-sensitive VBD can promote human health, building upon existing remote sensing with new focus on mosquito-borne arboviruses and tick-borne pathogens (Anaplasma, Rickettsia, Coxiella), including genomic analysis for hotspots of selection. Center function is supported by world-class transdisciplinary research environments and institutional commitment to community engagement and impact.