160 years after its clinical debut, general anesthesia is still a molecular mystery. Among its key targets are synaptic ligand-gated ion channels of the pentameric superfamily, including nicotinic acetylcholine and GABA(A) receptors. These proteins are also sensitive to modulators such as cholesterol. Computational biophysics is an unrivaled tool to unravel the molecular mechanism of those processes, however, our efforts were long frustrated by the lack of resolved structures. In the past few years, a steady trickle of structures have begun to appear, and the question for biophysicists has shifted to extracting biological meaning from these structures. This has turned out to be extremely challenging, ushering an era of exciting new understanding as well as renewed causes for frustration.