An important goal of modern biology is to formulate predictive models that will eventually enable re-engineering of organisms with predictable outcomes.  Such models will catalyze targeted drug discovery, molecular engineering of organisms for environmental clean up, production of better antibiotics, and other biotechnological applications of similar scale.  We have applied a systems approach to construct such a model for the extremophile Halobacterium salinarum NRC-1, from a hypersaline environment.  Using relative changes in 72 transcription factors, 9 environmental factors and their predicted regulatory influences, this model reconstructs changes in ~80% of the transcriptome during cellular responses to new genetic and environmental perturbations.  Through experimental verifications of several previously uncharacterized gene regulatory circuits we demonstrate that this model has captured a systems-level perspective of dynamic regulatory associations among diverse physiological processes.  Our findings suggest that the high degree of connectivity in biological networks and the physicochemical relationships among environmental factors make it possible to comprehensively model global cellular responses to diverse perturbations with a relatively small number of experiments.