Primary open-angle glaucoma (POAG) is a primary neuronal disease of the optic nerve without a definable cause, and is often associated with increased intraocular pressure. Worldwide, POAG is the second leading cause of blindness; there are 45 million people today with POAG and bilateral blindness is present in 4.5 million of these. In order to elucidate the possible etiologic factors in POAG, we have cataloged all known biomarkers in the aqueous humor, trabecular meshwork, optic nerve and blood into four categories, namely extracellular matrix (ECM), cell signaling molecules, aging/stress and immunity-related changes. We present a theoretical model to show possible signaling pathways of the ECM, cell signaling and innate immune response through activation of Toll-like receptor 4. Our article suggests that ECM and innate immune biomarkers are the lead candidates for developing the 'POAG biomarker signature'. We suggest that current research is critical to pinpoint the causes of the disease so that new treatment modalities can become available for better regulation of the intraocular pressure and neuroprotection of the optic nerve.