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Trace amine-associated receptor 1 (TAAR1) is a novel target for antipsychotic and potentially mood-stabilizing and anti-addictive drugs, offering a new mechanism by modulating dopaminergic, serotonergic, and glutamatergic neurotransmission. TAAR1 agonists from a prior amino oxazolines series were studied preclinically and clinically, but development of partial agonist RO5263397 was halted due to poor metabolization by N-glucuronidation in individuals with UGT2B10 splice site mutations. A medicinal chemistry program subsequently identified new potent and selective TAAR1 ligands from the morpholine series. Two selective partial agonists, RO6799477 and RO6889450, were advanced and showed antipsychotic, stress-response-modulating, and anti-addictive-like activity in rodent models. They reduced PCP- and cocaine-induced hyperlocomotion, potentiated olanzapine's effect, partially reversed cocaine-induced facilitation of intracranial self-stimulation and demonstrated anxiolytic-like properties in the stress-induced hyperthermia test. Neural activation profiles, measured by pharmacological MRI, differed from first and second-generation antipsychotics. Non-clinical drug abuse liability studies with RO6889450 indicated a favorable low abuse liability profile and suggested a lack of reinforcing effects. Preclinical safety studies indicated a favorable profile with clinically monitorable and reversible findings. Both compounds progressed into Phase I single and multiple ascending dose studies in healthy volunteers. RO6799477 was well tolerated, with rapid absorption and dose-proportional pharmacokinetics, though higher doses led to nervous system and cardiovascular adverse events. RO6889450 was well tolerated up to 300 mg; at 450 mg, dose-limiting adverse events included postural tachycardia and erythema. Together, these results indicate the translational potential and support further clinical exploration of TAAR1 agonists as a novel therapeutic option for neuropsychiatric disorders, particularly schizophrenia and substance use disorder.