Orthodontic tooth movement (OTM) requires the orthodontic forces (compressive and tensile strain) to subject to the periodontal ligament and mechanosensory cells in the periodontium and to achieve mechanotransduction by mechanoreceptors. In the context of OTM, a diverse array of signaling pathways are activated in mechanosensory cells that modulate bone resorption and formation in and models. The underlying molecular signal transduction, such as MAPK and β-Catenin signaling, that is involved in OTM, has been partially identified. It includes, but is not limited to genes and proteins which are related to osteogenesis, osteoclastogenesis, cementogenesis and inflammation. However, the interactive relation of β-Catenin and MAPK signaling remains ambiguous and diverse cross-talks are acting with each other. In this comprehensive text, we review the biology of OTM and reported experimental results on the activation/inhibition of these two signaling pathways during OTM. Here, we also focus on the implications and interplays between the MAPK and β-Catenin signaling in mechanosensory cells in response to orthodontic forces. Finally, the potential of further investigation strategies aimed at supporting orthodontic interventions are discussed. This review provides a conceptual framework for more comprehensive knowledge about signaling interaction during OTM.