Mechanotransduction is defined as the molecular process of transmitting an extracellular physical cue into an intracellular biochemical signal. Throughout the history of dental science, mechanobiology, i.e., the study of tissue and cell responses to physical stimuli, has long been neglected. There is, however, increasing experimental evidence to suggest that the complex interplay between biophysical forces with traditional biochemical signalling is pivotal for tissue integrity and homeostasis in the oral cavity. Periodontal tissues, namely the gingiva, periodontal ligament, cementum and alveolar bone, are permanently subjected to mechanical stimuli. The latter can arise from natural processes like chewing, or orthodontic appliances. The term ‘orthodontic tooth movement’ describes the movement of teeth within the dental alveoli in response to forces exerted by orthodontic appliances. Orthodontic tooth movement is a macroscopic term that subsumes all the molecular, mechanobiology-related signalling cascades that enable the adaptation of the periodontium during orthodontic treatment. Here, cells such as mesenchymal stem cells and periodontal ligament fibroblasts respond to external forces by modulating the activity state and spatial distribution of mechanotransducing proteins like focal adhesion kinase and the cotranscriptional activator yes-associated protein. The signalling activity of these proteins leads to changes in cellular behaviour, inducing cellular responses like proliferation, differentiation and migration. In the future, exact determination of the fine-tuning and integration of mechanobiological and biochemical factors will help to achieve a better understanding of periodontal physiology and pathophysiology and improve clinical orthodontic treatment by considering the molecular principles of mechanotransduction. This mini review therefore summarises current findings in periodontal mechanobiology, with a special focus on the above-mentioned molecules.