The links between loneliness and mortality are well-established. However, the biological pathways that are responsible for such links are less clear. This chapter reviews the evidence linking loneliness to major peripheral biological systems influencing disease risk, including the autonomic, neuroendocrine, and immune systems. There appears to be evidence linking loneliness to higher cardiovascular reactivity, flatter cortisol slopes, lower oxytocin, poorer cellular immune responses, and greater inflammatory gene expression. Critical future areas of inquiry include the need to test antecedent processes, mechanisms, clarifying less consistent findings (e.g., inflammatory markers), additional biological pathways (e.g., microbiome), and testing appropriate interventions.