Skeletal muscle tissue represents a unique opportunity to study gene regulatory phenomena in adult humans. The structural and functional plasticity of skeletal muscle tissue with regard to exercise conditions, microgravity, and other stimuli have been studied extensively over the past forty years and continue to be of interest. It has been established that standardized exercise interventions lead to typical structural and functional modifications. Increases in mitochondrial volume of over forty percent can be achieved in previously untrained subjects in training studies with a total exercise duration of only fifteen hours over a period of six weeks. These rapid and massive changes in muscle tissue protein composition have been shown over the past ten years to be dominantly (but not exclusively) controlled by gene regulatory phenomena. The muscle cells rely on external mechanical, metabolic, neuronal and metabolic signals which are specifically sensed and transduced over multiple pathways to the muscle genome. In exercise, many of these sensory and stimuli-dependent signaling cascades are activated, the individual characteristic of the stress leading to a specific response of a network of signaling pathways. Signaling typically results in the transcription of multiple early genes among those of the well known fos and jun families, as well as many other transcription factors. These bind to the promoter regions of downstream genes initiating the structural response of muscle tissue. While signaling is a matter of minutes, early genes are activated over hours leading to modifications of structural genes that can then be effective over days. The multiplicity of the signaling pathway and of the early gene activation leads to a bewildering complexity of possible genomic responses. This response is further tailored by “structural” genes having promoter regions capable of recognizing a host of activators and depressors. The current molecular techniques are in principle capable of dealing with the task of unraveling the enormous complexity of the events of genomic response to external stimuli. Changes over the entire human transcriptome can be assessed with appropriate array technologies, and proteomic approaches are rapidly being developed. The ultimate challenge will be to extract the biologically relevant information and to integrate this information into models of system physiologic relevance.