This review summarises recent progress in understanding crassulacean acid metabolism (CAM) systems and the integration of internal and external stimuli to maximise water-use efficiency. Complex CAM traits have been reduced to their minimum and captured as computational models, which can now be refined using recently available data from transgenic manipulations and large-scale omics studies. We identify three key areas in which an appropriate choice of modelling tool could help capture relevant comparative molecular data to address the evolutionary drivers and plasticity of CAM. One focus is to identify the environmental and internal signals that drive inverse stomatal opening at night. Secondly, it is important to identify the regulatory processes required to orchestrate the diel pattern of carbon fluxes within mesophyll layers. Finally, the limitations imposed by contrasting succulent systems and associated hydraulic conductance components should be compared in the context of water-use and evolutionary strategies. While network analysis of transcriptomic data can provide insights via co-expression modules and hubs, alternative forms of computational modelling should be used iteratively to define the physiological significance of key components and informing targeted functional gene manipulation studies. We conclude that the resultant improvements of bottom-up, mechanistic modelling systems can enhance progress towards capturing the physiological controls for phylogenetically diverse CAM systems in the face of the recent surge of information in this omics era.