Traumatic brain injury continues to be the silent epidemic of our times. It does not respect age or sex, although the epidemiological profile varies according to these parameters and the environment (low- or high-income countries). As a result of the energy absorbed by the post-traumatic brain parenchyma, the so-called primary injury develops, which in turn triggers the molecular signals of a series of events that will have local and systemic repercussions. Among these mechanisms, inflammation, excitotoxicity, lipid peroxidation, and the release of free oxygen radicals stand out. Additionally, sympathetic tone increases as a consequence of the massive release of adrenergic catecholamines while cortisol levels rise simultaneously. Secondary injury is a set of potentially damaging phenomena that can originate in the brain itself or in distant organs. Secondary insults aggravate and perpetuate primary damage but are characterized by being reversible, preventable, and modifiable. Tertiary injury occurs as a consequence of the potential adverse effects of the measures adopted for patient care, while quaternary injury has a strong genetic load which maintains the mechanisms of long-term damage or prevents cellular recovery phenomena. The brain is not isolated either anatomically or humorally, which is why it interacts permanently and distally with the rest of the body’s organs. This complex and bilateral communication network has been generically called “crosstalk” and includes different cellular, nervous, and humoral signals which, although they tend to maintain homeostasis in physiological situations, in the event of trauma they can worsen in different ways the initial traumatic damage and the results in terms of functionality or survival.