Advances in magnetic resonance spectroscopy (MRS) methodology and related analytic strategies allow sophisticated testing of neurobiological models of disease pathology in psychiatric disorders. An overview of principles underlying MRS, methodological considerations, and investigative approaches is presented. A review of recent research is presented that highlights innovative approaches applying MRS, in particular, hydrogen MRS, to systematically investigate specific psychiatric disorders, including autism spectrum disorders, schizophrenia, panic disorder, major depression, and bipolar disorder.