The ultimate goal of tool development is application in contexts of disease therapies and/or to address basic biological questions. Bioluminescent optogenetics (BL-OG) tools, molecular reagents that utilize light emitted by a luciferase when interacting with its luciferin to activate light-sensing molecules, have been employed in both areas. BL-OG was successfully used in preclinical, translational studies in animal models of epilepsy, peripheral nerve and spinal cord injury, stroke, neurodegenerative diseases, sleep disorders, diabetes, and various forms of cancer. Basic science studies were conducted in areas, including neurodevelopment, memory and learning, sngception, fear and anxiety, and the dissection of motor circuitry. All applications benefited from the advantages of BL-OG over standard optogenetic and chemogenetic approaches, particularly its noninvasiveness, spatial access, and fast kinetics and absence of cross-reactivity of luciferins. Moreover, BL-OG applications will increasingly enable unique capabilities not afforded by any currently available technology, such as bimodal opto- and chemogenetic activation, genetically targeted cell-to-cell communication, and integration of intracellular states with cellular outcomes. The studies reviewed in this chapter highlight the potential of BL-OG for therapeutic and fundamental basic science applications.