Current models of self-regulation theorize that the capacity to exert self-control draws upon a limited resource that, when depleted, increases the likelihood of giving in to unwanted (and many times unhealthy) impulses and behaviors. Initially, effects of depletion on self-regulatory strength were observed behaviorally, without reference to neurobiological mechanisms that might underlie these effects. Recently, researchers in the social brain sciences have proposed three accounts of the neural effects of depletion on self-regulatory strength. One view suggests that depletion primarily interferes with executive functioning and disrupts top-down control processes that would otherwise regulate impulses. A second view claims that depletion intensifies desires and amplifies activity associated with reward processing and impulse strength. The third account contends that depletion affects both reward systems and regulatory functioning in prefrontal cortex. In this chapter, we discuss how these accounts offer insights into potential neural mechanisms by which depletion weakens self-regulatory strength and leads to subsequent self-control failure. Then, we explore the possibility of improving self-regulatory strength, both in the short and long term. Specifically, we propose that self-regulatory capacity may be improved over time, with corticostriatal networks serving as targets of self-control training. Such training programs not only would help test the brain-based accounts discussed here but might benefit those populations who are especially prone to self-regulation failure.