Self-regulation denotes the processes by which people initiate, maintain, and control their own thoughts, behaviors, or emotions to produce a desired outcome or avoid an undesired outcome. Self-regulation brings the influence of distal factors such as biology, temperament, and socialization history onto cognition, motivation, and behavior. Dysfunction in self-regulation represents a contributory causal factor for psychopathology. Accordingly, we previously proposed a risk phenotype model for depression drawing from regulatory focus theory and traditional task-based fMRI studies. In this article, we revise and expand our risk phenotype model using insights from new methodologies allowing quantification of individual differences in task-free macroscale brain organization. We offer a set of hypotheses as examples of how examination of intrinsic macroscale brain organization can extend and enrich investigations of self-regulation and depression. In doing so, we hope to promote a useful heuristic for model development and for identifying transdiagnostic risk phenotypes in psychopathology.