Bioreactors are noted for their dynamic behavior deviant from that of chemical reactors because of metabolic regulation. Consequently model-based control of bioreactors must rely on models that can accommodate regulatory behavior. Although the framework of kinetics, the hallmark of analysis of all chemical reaction systems (of which metabolism is but an illustrious member), would be a natural implement for describing biological processes, its facileness has suffered at the hands of regulatory phenomena. In this paper, we review the cybernetic modeling effort of Ramkrishna and coworkers that has had a notable run of success in dealing with the diverse effects of metabolic regulation in numerous microbial processes. These effects include multiplicity of steady states of widely varying physiological activity, transient behavior traversing through multiple domains of metabolic shifts, and so on. This review will expound the basic tenets of the cybernetic framework in its current state of evolution, highlight the various developments of this methodology, and in effect, foster its future for model-based control of bioreactors towards maintaining a meticulously monitored metabolic activity. (C) 2003 Elsevier Ltd. All rights reserved.