Tooth movement by orthodontic force application is dependent on remodeling in periodontal ligament and alveolar bone, involving the activation of complex cellular and molecular mechanisms correlated with several macro- and microscopic biological changes. The orthodontic process involves the activation of many complex cellular and molecular mechanisms mediated by the release of chemical substance cascades by many cells of the periodontium. Mainly during the early stage of application of orthodontic forces, an inflammatory process can occur in the periodontium as a physiological response to the tissue stress. Several potential biomarkers of the biological alterations after an orthodontic force application expressing bone resorption and formation, periodontal ligament changes, and vascular and neural responses, may be detected. The appropriate choice of the mechanical force to achieve the highest rate of tooth movement in the shortest time of treatment avoiding adverse consequences is a primary objective of a specialist. Thus, an insight into the biological phenomena occurring during the orthodontic therapies by evaluating these biomarkers may be quite relevant for the clinicians. In this chapter, two models of study, i.e., mice and men, were used to describe the clinical usefulness of some biomarkers in orthodontics.