Combining contributions from engineering and medicine, we highlight the biomechanical turning points in the historical evolution of the intramedullary nailing stabilization technique and discuss the recent innovations concerning increase in bone-implant system stability. Following the earliest attempts, where stabilization of long bone fractures was purely based on intuition, intramedullary nailing evolved from allowing alignment and translational control through press-fit fixation to current clinical widespread acceptance marked by the mechanical linkage between nail and bone with interlocking screws that allow alignment, translation, rotation, and length control. In an attempt to achieve an optimum interfragmentary mechanical environment, recent improvements considered the impact of different biomaterials on bone-implant stiffness. Another strategy considered the increase in the structural stability through the reduction of the number of movements between the different components that constitute the bone-implant system. Intramedullary nail improvements will most likely benefit from merging mechanics and fracture-healing biology by combining surface engineering with sensor tools associated with the innovative progress in wireless technology and with bone-healing biological active agents. Future research should aim at better understanding the ideal mechanobiological environment for each stage of fracture healing in order to allow for intramedullary nail design that satisfies such requirements.