Recently, the rapid advancements in tissue optical clearing technology have brought new opportunities for modern orthopedic optical imaging research. Tissue optical clearing technology primarily reduces tissue light scattering and light absorption through various physical and chemical methods, allowing light energy to better spread in the tissue in order to increase the depth and contrast of optical imaging. Deeper and higher resolution bone tissue images and 3D spatial microstructure information can be obtained when combined with various fluorescence-labeling strategies, presenting a novel perspective and method for a breakthrough in the molecular imaging study of bone tissue with high scattering and bone disease. In this study, we will discuss the principle and mechanism of tissue optical clearing technology, focusing on the current state, most recent methods, and the mechanism of bone tissue clearing imaging, and prospect the possibility of using this technique in the molecular imaging of bone.