The prevalence and rising use of alcohol, opioids, and stimulants have led to substance use disorders (SUDs) that are a significant public health challenge. Traditional treatments offer some benefit; however, they often limited by efficacy, side effects, and accessibility, highlighting the urgent need for novel therapeutics. This review explores the current literature surrounding three different classes of novel treatments: glucagon-like peptide-1 (GLP-1) receptor agonists, dopamine D3 receptor (D3R) antagonists, and corticotropin-releasing factor (CRF) antagonists. These therapeutics collectively target different aspects of the addiction process, such as stress and relapse prevention, reward modulation, and the reduction of drug-seeking behavior, leading to a combined multifaceted approach to treating SUDs. This review includes preclinical and clinical evidence supporting the use of these therapies, highlighting their potential to reduce substance use and prevent relapse to alcohol, opioid, and stimulant use. Despite the potentially promising findings of these treatments, further research is necessary to fully understand their mechanisms, optimize their application, and confirm their efficacy in clinical settings.