The article discusses the rapidly changing landscape of ketamine in the United States, focusing on its use as a medical treatment and recreational substance. In 2019, the FDA approved esketamine, a form of ketamine, as the first antidepressant for treatment-resistant depression. This approval came with strict regulations, while ketamine remains largely off-label and unregulated. Despite this, the use of ketamine for depression has increased, with many practitioners offering it without oversight. The FDA has not approved ketamine for depression, and Medicare has not determined coverage for it, leading to uncertainty about its efficacy compared to esketamine. Ketamine is relatively cheap and easy to manufacture, making it more accessible illicitly than through medical settings. This has led to increased recreational use, with seizures and poisonings rising significantly. Illicit ketamine is often in powder form, which may be adulterated with other substances like fentanyl. The article highlights the need for further research and surveillance to monitor both medical and nonmedical use, off-label prescribing, and related adverse effects. It also emphasizes the importance of addressing ketamine diversion and trafficking, not just in psychiatric clinics but also in veterinary settings. Media coverage and advertising may influence shifts in use, and there is a need for more comprehensive surveillance to understand the current ketamine landscape and respond quickly to changes. The authors disclose potential conflicts of interest related to their affiliations and financial support.The article discusses the rapidly changing landscape of ketamine in the United States, focusing on its use as a medical treatment and recreational substance. In 2019, the FDA approved esketamine, a form of ketamine, as the first antidepressant for treatment-resistant depression. This approval came with strict regulations, while ketamine remains largely off-label and unregulated. Despite this, the use of ketamine for depression has increased, with many practitioners offering it without oversight. The FDA has not approved ketamine for depression, and Medicare has not determined coverage for it, leading to uncertainty about its efficacy compared to esketamine. Ketamine is relatively cheap and easy to manufacture, making it more accessible illicitly than through medical settings. This has led to increased recreational use, with seizures and poisonings rising significantly. Illicit ketamine is often in powder form, which may be adulterated with other substances like fentanyl. The article highlights the need for further research and surveillance to monitor both medical and nonmedical use, off-label prescribing, and related adverse effects. It also emphasizes the importance of addressing ketamine diversion and trafficking, not just in psychiatric clinics but also in veterinary settings. Media coverage and advertising may influence shifts in use, and there is a need for more comprehensive surveillance to understand the current ketamine landscape and respond quickly to changes. The authors disclose potential conflicts of interest related to their affiliations and financial support.