Isacoff works on the mechanisms of function of ion channels and neurotransmitter receptors, the molecular basis of synaptic transmission and plasticity, and the development of neural circuits. His work elucidated the basis of voltage sensing and gating of voltage-gated channels and enzymes. A major emphasis of the lab has been complementary efforts in imaging and optogenetic manipulation of neuronal activity and synaptic transmission. Isacoff developed the means to image excitatory synaptic transmission with quantal resolution with the signal-to-noise of electrophysiological measurement but with spatial information of synapse identity, methods with which he discovered an unexpected heterogeneity in synaptic strength, plasticity, and synaptic homeostasis. Isacoff’s Photoswitched Tethered Ligands provide optical control of neural firing and synaptic transmission with opto-chemical toggles that agonize, antagonize or block ion channels, ionotropic receptors and neuromodulatory G protein coupled receptors on the sub-millisecond time-scale. This approach has opened a novel branch of optogenetics that enables synaptic connections to be probed in real-time in intact circuits at multiple scales, from single dendritic spines to genetically select cells within whole brain regions. An applied effort of chemical optogenetics has been to create a treatment for blindness by installing light sensitivity into surviving retinal layers following photoreceptor cell degeneration.