Medications to treat substance use disorders (SUDs) remain suboptimal or, in the case of stimulants and cannabis, non-existent. Many factors have contributed to this paucity, including the biological complexity of addiction, regulatory challenges, and a historical lack of enthusiasm among pharmaceutical companies to commit resources to this disease space. Despite these headwinds, the recent opioid crisis has highlighted the devastating consequences of SUDs for both individuals and society, stimulating urgent efforts to identify novel treatment approaches. In addition, several neurobiological systems have been recently implicated in unique aspects of drug reward, opening the door to candidate medications with novel mechanisms of action. Here, we provide an overview of efforts to target several of these new systems, with a focus on those that are the subject of ongoing clinical trials as well as being areas of interest among the authors' research groups (MHJ, MTB, NAE). Specifically, we discuss new classes of medications targeting the serotonin 2A receptor (i.e., psychedelics), glucagon-like peptide 1 receptor, cannabidiol, dynorphin/kappa opioid receptor, orexin/hypocretin, and oxytocin receptor systems, as well as emergent approaches for modulating the more canonical dopaminergic system via agonist therapies for stimulant use disorders. Collectively, innovations in this space give reason for optimism for an improved therapeutic landscape for substance use disorders in the near future.