Excited to share our Cross-Species Single-cell Atlas of the Human Brain's Striatum, the brain region that integrates action planning, reward, motivation, decision-making, movement, learning, and reinforcement, implicated in schizophrenia, depression, addiction, and Huntington's Disease: authors.elsevier.com/c/1niW9… Our map spans 109 samples, 69 donors, and 670,000 nuclei. We identify 31 neuronal subpopulations, including 9 types of medium spiny neurons, and rare D1 interface MSNs forming island-like structures. Patch-clamp recordings show outlier MSNs have smaller somata and stronger hyperpolarization-activated currents than their neighbors. We show that the dorsolateral-ventromedial gradient shapes: receptor repertoires, disease gene expression, vulnerability. Across 124 GWAS, we show genetic risk for neuropsychiatric, cognitive and addiction traits concentrates in MSNs and is depleted in glia and vascular cells. Schizophrenia, bipolar and ADHD risk genes are dorsally enriched, and so, unexpectedly, are opioid use disorder risk genes — even though opioid signaling itself is ventrally biased, suggesting heritable risk and acute drug action may engage different parts of the striatum. Only a quarter of the human gradient genes are similarly zonated in mice. Several drug targets sit in different cells across species, including the mu-opioid receptor, the M5 muscarinic receptor, and the GLP-1 receptor, with important implications for preclinical screening. Profiling chronic antipsychotic exposure in mice, we find the transcriptional response strongly biased toward ventral MSNs. Finally, we connect genotype to phenotype at single-cell resolution. Our new method, scMOSAIC, reads HTT CAG repeat length and gene expression from the same nucleus — and finds that repeat length varies along that same dorsolateral-ventromedial axis. Huge congrats to Raleigh Linville @LinvilleRaleigh , Benjamin James @__ben_james__ , who carried this from start to finish, and to co-senior authors #MyriamHeiman and #DanaGabuzda, and Kiki Galani, Li-Lun Ho, Stu Fass, James Cameron, Brent Fitzwalter, Erica Engelberg-Cook, Sebastian Pineda, Dennis Dickson, Deborah Mash, Gustavo Turecki, Vanessa Wheeler, and Veronica Alvarez, across Massachusetts Institute of Technology, The Picower Institute for Learning and Memory, MIT Computer Science and Artificial Intelligence Laboratory (CSAIL), Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, The National Institutes of Health, Mass General Brigham, Mayo Clinic, McLean Hospital, McGill University, and beyond. Huge thanks to the #SCORCH consortium and the brain banks in the US and Canada, and a huge thanks to the donors and their families. Every cell in this atlas came from someone who decided their brain should go on being useful. The data are public, and we hope other labs take them further than we can.