Bone is one of the most adaptable tissues in the body as it is continuously subjected to load bearing. In fact, mechanical loading is an important regulator of bone mass. The skeleton adjusts to load by changing its mass, shape and microarchitecture, depending on the magnitude of the strain. Mechanical stimulation is necessary for the development of the skeleton, whereas in adults physiological levels of strain help maintain bone mass by reducing bone resorption. On the other hand, an excessive level of strain or bone disuse induces bone loss. Osteocytes are long-lived cells comprising more than 90% of bone cellularity, which are embedded in the bone matrix forming a functional syncytium extending to the bone surface. These cells are considered to be the main bone cells responsible for translating mechanical strain into regulatory signals for osteoblasts and osteoclasts, leading to adapting bone responses to environmental changes. In this review, we discuss the complexity and well-orchestrated events that occur in bone mechanotransduction, focusing on osteocyte viability as an important biological response in this respect. Elucidation of the molecular mechanisms of bone mechanotransduction and the key role of osteocytes is opening new avenues for the treatment of bone loss-related diseases.