Reversible chemical modification of enzymes is one of the most important mechanisms in cellular signaling. We generalize this concept to include cyclic modification of enzyme conformations. The mechanism is fundamentally different from the ligand induced conformational change: It only requires a catalytic amount of ligand to activate an enzyme, but it does require an active chemical energy driving a "futile cycle" akin to the phosphorylation-dephosphorylation cycle. The mechanism covers several previously proposed models that include serial engagement for T-cell receptor activation, energy relay for proofreading in DNA replication and protein biosynthesis, the hysteretic enzyme, and Fischer's hypothesis on protein tyrosine phosphatase action. While for small proteins operating under a funnel-shaped energy landscape, multiple conformations with sufficiently long dwell times are not common, recent experiments suggest that for larger, multidomain proteins, cyclic conformational modification (CCM) is much more likely and evolution presumably finds a way to capitalize on this mode of regulation. CCM can be difficult to identify in cells; however, it is potentially an important, and yet overlooked, regulatory mechanism in cellular signal transduction. We suggest the serial engagement mechanism in T-cell activation to be a possible testing case for the CCM mechanism.