The musculoskeletal system is an integral part of the human body. Currently, most skeletal muscle research is conducted through conventional histological sections due to technological limitations and the structure of skeletal muscles. For studying and observing bones and muscles, there is an urgent need for three-dimensional, objective imaging technologies. Optical tissue-clearing technologies seem to offer a novel and accessible approach to research of the musculoskeletal system. Using this approach, the components which cause refraction or prevent light from penetrating into the tissue are physically and chemically eliminated; then the liquid in the tissue is replaced with high-refractive-index chemicals. This innovative method, which allows three-dimensional reconstruction at the cellular and subcellular scale, significantly improves imaging depth and resolution. Nonetheless, this technology was not originally developed to image bones or muscles. When compared with brain and nerve organs which have attracted considerable attention in this field, the musculoskeletal system contains fewer lipids and has high levels of hemoglobin, collagen fibers, and inorganic hydroxyapatite crystals. Currently, three-dimensional imaging methods are widely used in the diagnosis and treatment of skeletal and muscular illnesses. In this regard, it is vitally important to review and evaluate the optical tissue-clearing technologies currently employed in the musculoskeletal system, so that researchers may make an informed decision. In the meantime, this study offers guidelines and recommendations for expanding the use of this technology in the musculoskeletal system.