Human activities, primarily the burning of fossil fuels, widespread deforestation, soil erosion or machine-intensive farming methods, manufacturing, food processing, mining, construction, and the iron, cement, steel, and chemicals industries, have been the main drivers of the observed increase in Earth's average surface temperature and climate change. Rising global temperatures, extreme weather events, ecosystems disruption, agricultural impacts, water scarcity, problems in access to good quality water, food and housing, and profound environmental disruptions such as biodiversity loss and extreme pollution are expected to steeply increase the prevalence and severity of acute and chronic diseases. Its long-term effects cannot be adequately predicted or mitigated without a comprehensive understanding of the adaptive ecosystems. Studying the complex interaction between environmental aggressors and the resilient adaptive responses requires the exposomic and the One Health approaches. The problem is broad and affects the whole ecosystem, plants, pets, and animals in addition to humans. The central role of the epithelial barrier, microbiome, and diet as key pillars for an adaptive tolerogenic immune response should be explored for increasing resilience at the individual level. A radical change in mindset worldwide, with sustainable solutions and adaptive strategies and climate resilience and health equity policies at their center, should be achieved quickly through increased awareness based on solid scientific data.