Despite intense research, the pathogenesis of primary open-angle glaucoma (POAG) is still not completely understood. There is ample evidence for a pathophysiological role of elevated intraocular pressure; however, several systemic factors may influence onset and progression of the disease. Systemic peculiarities found in POAG include alterations of the cardiovascular system, autonomic nervous system, immune system, as well as endocrinological, psychological, and sleep disturbances. An association between POAG and other neurodegenerative diseases, such as Alzheimer disease and Parkinson disease, has also been described. Furthermore, the diagnosis of glaucoma can affect the patient's quality of life. By highlighting the systemic alterations found in POAG, this review attempts to bring glaucoma into a broader medical context.