One of the ultimate goal of systems biology is to realize a virtual cell system in the computer. If this could be attained, it might be possible, for example, to quantitatively predict the effects of a culture environment and/or the removal/inactivation of specific genes on the metabolism without conducting many experiments. Thus, it may be possible to design cells, e.g., for more efficient production of a specific metabolite. To achieve this, it is important to properly understand the metabolic regulation mechanism and to develop a robust model by incorporating gene-level regulation into the enzymatic reaction model with the integration of different levels of information. However, the metabolic regulation in response to the change in culture environment is itself not well understood. Here, we overview how the culture environment affects cell metabolism via global regulators with sigma factors, considering the effects of carbon, nitrogen, and phosphate sources as well as oxygen, temperature, pH, and nutrient stress, etc., on transcriptional regulation. A variety of controlled strategies for the specific stimuli imposed on the cell appear to exist, and some of the regulations are interconnected by gene level regulation. Quantitative modeling for these regulation mechanisms is critical for efficient metabolic engineering of a cell.