Specificity of exercise training is essential to promote the phenotypic adaptations crucial for optimal athletic performance. The main factor contributing to the specificity of adaptation in skeletal muscle is the mode of contractile activity, which is underpinned by the volume, intensity and frequency of the training stimulus. In this regard, the diverse functional and phenotypic profiles associated with endurance or resistance/power-based training are easy to discern, and the ‘molecular signatures’ associated with these distinct adaptations well described. However, characterising the molecular ‘footprint’ responsible for the ‘interference effect’ of endurance-based exercise on hypertrophy and strength when divergent exercise stimuli are undertaken concurrently (in the same training session or as part of a long-term training regimen) has proven problematic. Adding to the complexity of the molecular responses to concurrent exercise modes is the training background on which they are implemented. Divergent modes of exercise can induce similar gene expression and signalling profiles in skeletal muscle of untrained or recreationally active individuals, while chronic endurance or strength training attenuates some of the exercise specific signaling responses involved in single-mode adaptations to training. An important practical outcome of a ‘time-dependent training adaptation continuum’ is that it may be necessary to undertake divergent modes of exercise at different times during a periodised training program to induce the desired phenotype. Despite the potential for several key regulators of muscle metabolism to explain the incompatibility in adaptation between endurance and resistance exercise, the mechanistic underpinning of the ‘interference effect’ after concurrent training is not well understood. It seems likely that multiple integrated networks and pathways with a high degree of crosstalk and feedback regulation, rather than single isolated, effectors or processes underpin this phenomenon.