Light sources, including bioluminescence, have been used extensively to activate opsins, light-sensing ion channels, and pumps, to change membrane potential and thereby the function of neurons. However, opsins are but a small part of the vast pool of photoreceptors, proteins that contain light-sensing domains. Recruited from across phyla, these photosensory proteins enable light-driven conformational changes, dimerization, enzyme activation, or the generation of reactive oxygen species. Extension of the optogenetic approach to these non-opsin photoreceptors has enabled light control of intracellular processes for applications in cell and developmental biology as well as in therapeutic contexts. This review details the application of bioluminescence as the light source for activating non-opsin photoreceptors for control of biological processes from transcription to cell death. Key features of the design principles of the molecular tools, the intracellular processes targeted, and the applications in vitro and in vivo for proof-of-principle demonstrations and for therapeutic applications are described.