Hypertrophic osteoarthropathy (HOA) is a condition that accompanies many seemingly unrelated diseases. It is commonly associated with various clinical conditions such as pregnancy, aging, pulmonary diseases, cancers, and other systemic illnesses. The condition has been attributed to various causes such as platelet abnormalities, hormonal disturbances, and cytokine dysfunction, but the exact underlying mechanism has been elusive. We propose a unifying hypothesis that activation of the adrenergic system is the common thread that links all of the disparate clinical associations of hypertrophic osteoarthropathy. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. In this setting, clinical signs of HOA may be a marker of underlying autonomic dysfunction. Autonomic stimulation may also occur as a normal part of pregnancy or as an abnormal component of aging. The exact pathway linking adrenergic excess to HOA remains to be clarified, but a plausible scenario based on current molecular evidence is offered.