Optogenetic tools enable the optical perturbation of complex cellular physiology in intact tissue, by sensitizing genetically targeted cell populations via the heterologous expression proteins with known light-activated physiological effect. For example, arbitrary trains of action potentials can be optically elicited with millisecond resolution by depolarizing excitable cells expressing light-gated cation channels. The optogenetic toolbox is an incredibly rich one, enabling panoply of inducible physiological perturbations with spatio-temporal precision: depolarizing channels, hyperpolarizing pumps, GPCR’s, nucleotide cyclases, allosteric modulators of protein-protein interactions, among others. Ultimately, since they are commonly derived from lower organisms and microbes, innovation in optogenetic tool development has been greatly accelerated by genomic technologies, both in next-generation sequencing and de novo synthesis. This talk will cover the use of such genomic technologies as well as automated phenotyping systems for the discovery and molecular engineering of novel optogenetic tools, and their potential translational application toward a next-generation of neuromodulation devices to correct aberrant activity in neural circuits implicated in nervous system disorders and abnormal pathologies.