As a social species, humans rely on a safe, secure social surround to survive and thrive. Perceptions of social isolation, or loneliness, increase vigilance for threat and heighten feelings of vulnerability while also raising the desire to reconnect. Implicit hypervigilance for social threat alters psychological processes that influence physiological functioning, diminish sleep quality, and increase morbidity and mortality. The purpose of this paper is to review the features and consequences of loneliness within a comprehensive theoretical framework that informs interventions to reduce loneliness. We review physical and mental health consequences of loneliness, mechanisms for its effects, and effectiveness of extant interventions. Features of a loneliness regulatory loop are employed to explain cognitive, behavioral, and physiological consequences of loneliness and to discuss interventions to reduce loneliness. Loneliness is not simply being alone. Interventions to reduce loneliness and its health consequences may need to take into account its attentional, confirmatory, and memorial biases as well as its social and behavioral effects.