This article reviews key findings on stress, motivation, and pathological gambling (PG). Environmental and dispositional sources of stress that promote PG are described, along with effects of acute stressors on risk-based decision-making. Gambling itself has stress-like physiological effects, activating norepinephrine (NE), cortisol (CORT), and, in PG subjects, dopamine (DA). Chronic exposure to gambling could evoke neuroadaptations in these systems, and motivation to gamble in PG subjects may partly reflect an effort to restore homeostasis. Alpha-2 NE receptors tonically inhibit, and alpha-1 NE receptors augment, striatal DA release and hypothalamic-pituitary axis-mediated CORT response. Gambling-induced dysregulation of this circuitry, coupled with environmental and dispositional stressors, may lead to allostasis, sensitization, and disturbances in cognitive function that promote further gambling. Interventions that mitigate stress may therefore deter onset and restore control over compulsive motivation to gamble in individuals with PG.