Traumatic brain injury caused by explosive or blast events is traditionally divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic brain injury (bTBI) are biomechanically distinct and can be modeled in both in vivo and in vitro systems. The primary bTBI injury phase represents the response of brain tissue to the initial blast wave. Among the four phases of bTBI, there is a remarkable paucity of information about the cause of primary bTBI. On the other hand, 30 years of research on the medical application of shockwaves (SW) has given us insight into the mechanisms of tissue and cellular damage in bTBI, including both air-mediated and underwater SW sources. From a basic physics perspective, the typical blast wave consists of a lead SW followed by supersonic flow. The resultant tissue injury includes several features observed in bTBI, such as hemorrhage, edema, pseudoaneurysm formation, vasoconstriction, and induction of apoptosis. These are well-described pathological findings within the SW literature. Acoustic impedance mismatch, penetration of tissue by shock/bubble interaction, geometry of the skull, shear stress, tensile stress, and subsequent cavitation formation, are all important factors in determining the extent of SW-induced tissue and cellular injury. Herein we describe the requirements for the adequate experimental set-up when investigating blast-induced tissue and cellular injury; review SW physics, research, and the importance of engineering validation (visualization/pressure measurement/numerical simulation); and, based upon our findings of SW-induced injury, discuss the potential underlying mechanisms of primary bTBI.