Calcium-specific fluorescent indicators have been used to identify activated neurons, but these reporters are only passive tools that allow experimentalists to observe, but not to perturb, neuronal activity, and do not enable the alteration of gene expression to manipulate neuronal function and behavior. Lee et al. and Wang et al. developed two optogenetic systems, Cal-Light and FLARE, respectively, that rapidly label a neuronal population in the presence of both calcium signaling and light exposure. Both systems utilize a transcription factor that is tethered to a caged protease cleavage site adjacent to a light-sensitive LOV2 domain and a second protein that contains a protease linked to the calcium-sensing protein. An increase in calcium levels during neuronal activity promotes the dimerization of these two proteins, while blue-light exposure mediates a conformational change in the LOV2 domain to expose the cleavage site to processing by the neighboring protease. The released transcription factor then enters the nucleus to promote gene expression. Lee et al. infected mouse brains with a Cal-Light virus expressing halorhodopsin to silence neuronal activity with yellow-light exposure, which selectively suppressed lever-pressing motor behavior without perturbing other motor functions. Meanwhile, Wang et al. used their FLARE system to drive expression of a Chrimson–mCherry fusion protein that promoted action potentials in specific neurons upon red-light exposure. Altogether, both Cal-Light and FLARE systems offer exciting opportunities to discover, image, and manipulate functional neuronal circuits.