Novel psychoactive substances (NPS) emerged in the United States around 2000. Initially, synthetic cannabinoids and stimulants prevailed. Now, designer opioids, benzodiazepines and others have appeared. As a result of pain management, in addition to common drug abusers, a whole new set of individuals in desperate search for pain medications have become abusers of the NPS version of designer opioids helping spur the current opioid crisis in the United States. The adverse effects of NPS have become significant public health and public safety concerns. Adverse effects from these substances range from psychosis to death with abusers often committing crimes or injuring themselves. From a forensic toxicological concern, deaths from NPS are now commonplace. The landscape of these compounds changes frequently, making it difficult for toxicology laboratories to stay relevant. The analytical tools required are costly and laboratories need to constantly update the scope of compounds within the assay. The history of NPS, their associated effects and the breadth of the problem from social and scientific perspectives will be addressed along with future outlooks for this class of substances that have become a costly part of the drug use and abuse scenes in respect to lives lost and eradication.