The central paradigm of skeletal mechanobiology is that mechanical forces modulate morphological and structural fitness of the skeletal tissues—bone, cartilage, ligament and tendon. Traditionally, skeletal biomechanics has focussed on how these tissues perform the structural and locomotory functions of the vertebrate skeleton. In mechanobiology the central question is how these same load-bearing tissues are produced, maintained and adapted by cells as an active response to biophysical stimuli in their environment. The idea that ‘form follows function’ is not new, but we now believe that the scientific community has the knowledge and tools to prove, understand and use functional adaptation to benefit medicine and human health. In this Survey Article the philosophy and progress of skeletal mechanobiology are discussed. The revival of this science, with roots dating back to the 19th Century, is now driven by new developments in cellular, molecular and computational technologies. These developments are still in an early stage of application, but if modern mechanobiology fulfills the promises of its ambitions, the results will bring great benefits to tissue engineering and to the treatment and prevention of skeletal conditions such as congenital deformities, osteoporosis, osteoarthritis and bone fractures.