The cyclic nucleotide phosphodiesterases (PDEs) are a multifamily class of enzymes that have garnered significant attention in biotechnology and pharmaceuticals over ~30 years, with successful drugs for conditions like heart failure, COPD, erectile dysfunction, and pulmonary hypertension. PDE10A is a single-family phosphodiesterase highly expressed in the striatum, making it a prime target for neuroscience diseases involving striatal dysregulation. It has two splice variants (PDE10A1/A2) with distinct subcellular localizations and two GAF domains regulating catalytic activity. Selective PDE10A inhibitor 1 shows antipsychotic-like activity in preclinical models with reduced extrapyramidal side effects compared to D2 antagonists. PDE10A inhibitors activate both D1 direct and D2 indirect pathways, offering unique therapeutic potential. Preclinical data suggest potential for Huntington's disease, pulmonary hypertension, and metabolic diseases. Structure-based drug design leveraging the PDE10A selectivity pocket has led to potent inhibitors, some entering clinical trials. This review provides an overview of PDE10A's biological characteristics, inhibitor development, preclinical studies, and clinical progress.