The anterior cingulate cortex (ACC) is essential for monitoring ongoing behavior, regulating affect, and guiding social interactions. Altered ACC structure and function are implicated in a host of psychiatric disorders, most notably major depressive disorder. Thus, cross talk between basic and translational research is needed to drive the next generation of treatments. The human and nonhuman primate ACC is large and can be subdivided based on anatomical structure and connectivity. Increasingly, studies of the ACC point to unique functions for its distinct areas. This review highlights recent work aimed at understanding of the structure and function of distinct portions of the ACC and the role of these regions in cognition and affect in higher species. We focus on the roles and subregions that might guide the development of treatments for psychiatric disorders. This includes discussion of in-depth anatomical investigations that have revealed that distinct portions of the subgenual and perigenual ACC areas are driven by unique afferent paths. Furthermore, we describe neurophysiological recordings of single-neuron and local field potential activity, combined with carefully designed behavioral tasks or novel approaches to discerning affective states, which have revealed the neural mechanisms engaged in ACC during affective experience and assessment of conspecifics. We present noninvasive and invasive neuromodulation approaches that target the ACC to treat depression and have been shown to be most effective when they change activity within subgenual parts of ACC and may structurally remodel the connections of this area. Finally, we review new approaches to uncover upstream drivers and downstream effectors of ACC activity in higher species, including functional changes implicated in health, disease, and recovery.