Carbon dioxide (CO2) is a fundamental physiological gas known to profoundly influence the behaviour and health of millions of species within the plant and animal kingdoms in particular. A recent Royal Society meeting on the topic of 'Carbon dioxide detection in biological systems' was extremely revealing in terms of the multitude of roles that different levels of CO2 play in influencing plants and animals alike. While outstanding research has been performed by leading researchers in the area of plant biology, neuronal sensing, cell signalling, gas transport, inflammation, lung function and clinical medicine, there is still much to be learned about CO2-dependent sensing and signalling. Notably, while several key signal transduction pathways and nodes of activity have been identified in plants and animals respectively, the precise wiring and sensitivity of these pathways to CO2 remains to be fully elucidated. In this article, we will give an overview of the literature relating to CO2-dependent signal transduction in mammalian systems. We will highlight the main signal transduction hubs through which CO2-dependent signalling is elicited with a view to better understanding the complex physiological response to CO2 in mammalian systems. The main topics of discussion in this article relate to how changes in CO2 influence cellular function through modulation of signal transduction networks influenced by pH, mitochondrial function, adenylate cyclase, calcium, transcriptional regulators, the adenosine monophosphate-activated protein kinase pathway and direct CO2-dependent protein modifications. While each of these topics will be discussed independently, there is evidence of significant cross-talk between these signal transduction pathways as they respond to changes in CO2. In considering these core hubs of CO2-dependent signal transduction, we hope to delineate common elements and identify areas in which future research could be best directed.