The impacts of climate change are pervasive across the biosphere, stressing virtually all biotic kingdoms and supporting habitats. Contemporary lifeforms respond to climate stress and are early sentinels of how the biosphere could evolve over the longer term. Our capacity to detect biostress has improved markedly with new genetic, biochemical, and biogeochemical techniques; model organisms; ubiquitous in situ and remote sensors; simulations; artificial intelligence tools; socio-environmental perspectives; and global-scale data analytics. Based on these advancements, we present a conceptual climate biostress model, together with an integrative Climate BioStress Sentinel System (CBS3). The sentinel system represents a vehicle for uncovering synergistic and cumulative climate effects in urban settings and their biological, built, and social infrastructures. Developing an integrated CBS3 constitutes a pan-scientific grand challenge requiring integration across traditional disciplinary perspectives spanning at least 12 orders of magnitude each in space and time. By providing operational tracking of the success or failure of commitments to long-term climate and environmental action, CBS3 can provide insights into necessary policy investments and adjustments.