Progress made in basic research in the last decades led to a tremendous increase in quality of clinically applied bone substitute materials (polymers, ceramics and composites). The desired biological performance of these materials has consequently shifted from a passive role where materials were merely accepted by the body to an active role in which materials instruct their biological surroundings. Bone substitute materials were traditionally based on bioceramics, that can be optimized in terms of composition, structure and porosity. Now, polymers are increasingly gaining importance for use in medical applications due to their high versatility. This review provides an overview of the evolution from 1st generation biotolerant and bioinert materials via 2nd generation bioresponsive bone substitutes towards 3rd generation bioinstructive bone substitute materials that possess inherent biological cues for bone regeneration.