The primary focus of radiochemistry development for positron emission tomography (PET) and single photon emission computed tomography (SPECT) has been dopamine and serotonin neurotransmission. This chapter reviews the PET and SPECT neurochemical brain imaging studies to understand the neurochemical mechanisms underling depression and the response to treatment. It examines the clinical and methodological aspects involved in the design, analysis and interpretation of neurochemical imaging studies. The chapter overviews the studies on neurochemical imaging in depressive illness. While the majority of studies have focused on unipolar depression, the chapter discusses the available data on other depression subtypes. The serotonin and dopamine systems have been the major focus of in-vivo neurochemical imaging studies in depression, as well as other conditions including schizophrenia and anxiety disorders. The chapter also reviews the available neurochemical imaging data for other neurotransmitter systems, and highlights active areas of radiotracer development for other potentially important neurochemical targets.