The recent increase in radioligands available for neuroimaging major depressive disorder has led to advancements in our understanding of the pathophysiology of this illness and improved antidepressant development. Major depressive disorder can be defined as an illness of recurrent major depressive episodes of persistently low mood, dysregulated sleep, appetite and weight, anhedonia, cognitive impairment, and suicidality. The main target sites investigated with radioligand neuroimaging include receptor sites that regulate in response to lowered monoamine levels, targets related to removal of monoamines, uptake of ligands related to regional brain function, and target sites of antidepressants.