This article informs and updates the practicing neurologist on the current landscape of known neurologic injuries linked to the use of illicit drugs, focusing on emerging agents. Synthetic opioids such as fentanyl and similar derivatives have exploded in prevalence, becoming the leading cause of overdose fatalities. The higher potency of synthetic opioids compared with semisynthetic and nonsynthetic opiates poses an increased risk for unintentional overdose when found as an adulterant in other illicit drug supplies such as heroin. Conversely, misinformation about the risk of symptomatic exposure to fentanyl through casual contact with the skin and ambient air has led to misdirected fear and stigma that threatens to impede valid harm-reduction measures for fentanyl users at risk of actual overdose. Finally, during the COVID-19 pandemic, overdose rates and deaths continued to climb, especially among those who use opioids and methamphetamine. A variety of potential neurologic effects and injuries can occur with illicit drug use owing to the diverse properties and mechanisms of action of the various classes. Many high-risk agents are not detected on standard drug screens, including so-called designer drugs, and the practicing neurologist is best served by recognizing the clinical features of the traditional toxidrome and other potential idiosyncratic effects of various illicit agents.