Significance Sensory photoreceptors not only enable organisms to derive spatial and temporal cues from incident light but also provide the basis for optogenetics, which denotes the manipulation by light of living systems with supreme spatial and temporal resolution. To expand the scope of optogenetics, we have engineered the light-activated phosphodiesterase LAPD, which degrades the ubiquitous second messengers cAMP and cGMP in a red-light–stimulated manner. Both cAMP and cGMP are key to the regulation of manifold physiological responses, and LAPD now augurs red-light control over these processes. As we demonstrate for two eukaryotic systems, LAPD does not require any additional exogenous factors, and thus permits the light perturbation of living cells in hitherto unrealized ways.