Since the advent of chlorpromazine in the 1950s, D2 receptor antagonist activity has been synonymous with antipsychotic medications. This single mechanism of action may explain the similarities in efficacy among approved antipsychotics. Additionally, extrapyramidal and metabolic side effects of antipsychotics present a significant burden to patient quality of life. Development of the next generation of antipsychotics has focused on novel mechanisms of action including drugs that act through the N‐methyl‐d-aspartate (NMDA) system, modify second messenger activity, and modulate neuronal firing. This review surveys a selection of novel treatments with activity against positive symptoms. Each section includes a brief description of their mechanism of action, summarizes studies evaluating their clinical efficacy, and comments on safety and tolerability issues. Included in this review are compounds originally developed for treating psychotic disorders such as pimavanserin, pomaglumetad, and bitopertin. Other interventions are off-label uses of existing treatments such as bexarotene, rTMS, and sodium nitroprusside.