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Traumatic brain injury (TBI) is distinct from other neurological disorders because it is induced by a discrete event that applies extreme mechanical forces to the brain. This review describes how the brain senses, integrates, and responds to forces under both normal conditions and during injury. The response to forces is influenced by the unique mechanical properties of brain tissue, which differ by region, cell type, and sub-cellular structure. Elements such as the extracellular matrix, plasma membrane, transmembrane receptors, and cytoskeleton influence its properties. These same components also act as force-sensors, allowing neurons and glia to respond to their physical environment and maintain homeostasis. However, when applied forces become too large, as in TBI, these components may respond in an aberrant manner or structurally fail, resulting in unique pathological sequelae. This so-called “pathological mechanosensation” represents a spectrum of cellular responses, which vary depending on the overall biomechanical parameters of the injury and may be compounded by repetitive injuries. Such aberrant physical responses and/or damage to cells along with the resulting secondary injury cascades can ultimately lead to long-term cellular dysfunction and degeneration, often resulting in persistent deficits. Indeed, pathological mechanosensation not only directly initiates secondary injury cascades, but this post-physical damage environment provides the context in which these cascades unfold. Collectively, these points underscore the need to use experimental models that accurately replicate the biomechanics of TBI in humans. Understanding cellular responses in context with injury biomechanics may uncover therapeutic targets addressing various facets of trauma-specific sequelae.