Bioluminescence can be used for integrating intracellular activity states with user-defined changes in cellular function. Combining bioluminescent sensors, split luciferases whose light emission is dependent on the availability of an intracellular agent, with light-dependent actuators creates a Bioluminescent Activity-Dependent (BLADe) platform for converting biochemical signals within cells into photoreceptor activation and downstream cellular outcomes. To validate this experimental framework, a luciferase split by a calcium-sensing domain was used to convert neural activity into transcription of a reporter gene and into changes in membrane potential in vitro and in vivo. Facilitating the engineering of further BLADe sensors that couple biochemical events to light output motivated the molecular evolution of a new luciferase scaffold, SSLuc, that is highly amenable to insertion of sensor domains. This modular strategy of coupling an activity-dependent light emitter to a light-sensing actuator offers a generalizable framework for state dependent cell-autonomous control across biological systems.