© 2015, Elsevier Limited. All rights reserved. The ONH is of particular interest from a biomechanical perspective because it is a weak spot within an otherwise strong corneo-scleral envelope. Overwhelming evidence suggests that the lamina cribrosa is the principal site of retinal ganglion cell axon insult in glaucoma, so glaucomatous optic neuropathy can be viewed as an axonopathy occurring at the ONH. We present a framework of ONH biomechanics as a central mechanism in glaucoma pathophysiology, wherein IOP not only determines the mechanical environment in the ONH, but also mediates IOP-induced connective tissue remodeling, reductions in blood flow, and cellular responses through various pathways.