The search for more effective treatments for depression is a long-standing primary objective in both psychiatry and translational neuroscience. From initial models centered on neurochemical deficits, such as the monoamine hypothesis, research toward this goal has shifted toward a focus on network and circuit models to explain how key nodes in the limbic system and beyond interact to produce persistent shifts in affective states. To build these models, researchers have turned to two complementary approaches: neuroimaging studies in human patients (and their healthy counterparts) and neurophysiology studies in animal models, facilitated in large part by optogenetic and chemogenetic techniques. As the authors discuss, functional neuroimaging studies in humans have included largely task-oriented experiments, which have identified brain regions differentially activated during processing of affective stimuli, and resting-state functional MRI experiments, which have identified brain-wide networks altered in depressive states. Future work in this area will build on a multisite approach, assembling large data sets across diverse populations, and will also leverage the statistical power afforded by longitudinal imaging studies in patient samples. Translational studies in rodents have used optogenetic and chemogenetic tools to identify not just nodes but also connections within the networks of the limbic system that are both critical and permissive for the expression of motivated behavior and affective phenotypes. Future studies in this area will exploit mesoscale imaging and multisite electrophysiology recordings to construct network models with cell-type specificity and high statistical power, identifying candidate circuit and molecular pathways for therapeutic intervention.