The purpose of this paper is to review the most common and quickest growing classes of novel, or new, psychoactive substances. Abuse of novel psychoactive substances continues to increase, resulting in subsequent increases in hospitalizations. Furthermore, the chemical structures are ever-changing and substances are increasing in potency. Reviewing the chemistry behind these agents will facilitate a better understanding of the toxicity associated with them and allow for successful identification of and management in the critical care unit. Being familiar with the most common psychoactive substances and trends of abuse, as well as the challenges health care providers face when managing intoxication, is essential to the overall understanding and care of these critically ill patients.