Electroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT's effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT's proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT's efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain.