During the past two decades, a variety of serum or cerebrospinal fluid (CSF) biochemical markers in daily clinical practice have been recommended to diagnose and monitor diverse diseases or pathologic situations. It will be essential to develop a panel of biomarkers, to be suitable for evaluation of treatment efficacy, representing distinct phases of injury and recovery and consider the temporal profile of those. Among the possible and different biochemical markers, S100b appeared to fulfill many of optimized criteria of an ideal marker. S100b, a cytosolic low molecular weight dimeric calcium-binding protein from chromosome 21, synthesized in glial cells throughout the CNS, an homodimeric diffusible, belongs to a family of closely related protein, predominantly expressed by astrocytes and Schwann cells and a classic immunohistochemical marker for these cells, is implicated in brain development and neurophysiology. Of the 3 isoforms of S-100, the BB subunit (S100B) is present in high concentrations in central and peripheral glial and Schwann cells, Langerhans and anterior pituitary cells, fat, muscle, and bone marrow tissues. The biomarker has shown to be a sensitive marker of clinical and subclinical cerebral damage, such as stroke, traumatic brain injury, and spinal cord injury. Increasing evidence suggests that the biomarker plays a double function as an intracellular regulator and an extracellular signal of the CNS. S100b is found in the cytoplasm in a soluble form and also is associated with intracellular membranes, centrosomes, microtubules, and type III intermediate filaments. Their genomic organization now is known, and many of their target proteins have been identified, although the mechanisms of regulating S100b secretion are not completely understood and appear to be related to many factors, such as the proinflammatory cytokines, tumor necrosis factor alpha (TNF-a), interleukin (IL)-1b, and metabolic stress.