Deep Brain Stimulation (DBS), the targeted modulation of discrete neural circuits using implanted electrodes, is an experimental treatment strategy for patients with intractable depression and other neuropsychiatric disorders. While various brain targets are being investigated, progress to optimize and refine DBS to the subcallosal cingulate region (SCC) for depression has continued to evolve and mature, with a growing focus on multimodal readouts to guide clinical decisions over time.  Enabled by advances in device technology and supported by animal models, recent studies are now implementing combined multimodal imaging with dense time-series electrophysiological and naturalistic behavioral data to track the trajectory of treatment response and characterize circuit plasticity and repair during acute and chronic stimulation.  The use of these complementary perspectives is yielding a more cohesive understanding of disease pathophysiology and DBS mechanisms of actions with implications beyond depression.