Since the 1990s, there has been waning interest in researching general anesthetics (anesthetics). Although currently used anesthetics are mostly safe and effective, they are not without fault. In pediatric populations and neonatal animal models, they are associated with learning impairments and neurotoxicity. In an effort to research safer anesthetics, we have gone back to reexamine neuroactive steroids as anesthetics. Neuroactive steroids are steroids that have direct, local effects in the central nervous system. Since the discovery of their anesthetic effects, neuroactive steroids have been consistently used in human or veterinary clinics as preferred anesthetic agents. Although briefly abandoned for clinical use due to unwanted vehicle side effects, there has since been renewed interest in their therapeutic value. Neuroactive steroids are safe sedative/hypnotic and anesthetic agents across various animal species. Importantly, unlike traditional anesthetics, they do not cause extensive neurotoxicity in the developing rodent brain. Similar to traditional anesthetics, neuroactive steroids are modulators of synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors and their interactions at the GABAA receptor are stereo- and enantioselective. Recent work has also shown that these agents act on other ion channels, such as high- and low-voltage-activated calcium channels. Through these mechanisms of action, neuroactive steroids modulate neuronal excitability, which results in characteristic burst suppression of the electroencephalogram, and a surgical plane of anesthesia. However, in addition to their interactions with voltage and ligand gated ions channels, neuroactive steroids interact with membrane bound metabotropic receptors and xenobiotic receptors to facilitate signaling of pro-survival, anti-apoptotic pathways. These pathways play a role in their neuroprotective effects in neuronal injury and may also prevent extensive apoptosis in the developing brain during anesthesia. The current review will explore the history of neuroactive steroids as anesthetics in humans and animal models, their diverse mechanisms of action, and their neuroprotective properties.