Osteoblasts are key components of the bone multicellular unit and have a seminal role in bone remodeling, which is an essential function for the maintenance of the structural integrity and metabolic capacity of the skeleton. The coordinated function of skeletal cells is regulated by several hormones, growth factors and mechanical cues that act via interconnected signaling networks, resulting in the activation of specific transcription factors and, in turn, their target genes. Bone cells are responsive to mechanical stimuli and this is of pivotal importance in developing biomechanical strategies for the treatment of osteodegenerative diseases. Here, we review the molecular pathways and players activated by mechanical stimulation during osteoblastic growth, differentiation and activity in health, and consider the role of mechanostimulatory approaches in treating various bone pathophysiologies.