Over the last 4 decades innovations in biomaterials and medical technology have had a sustainable impact on the development of biopolymers, titanium/stainless steel and ceramics utilized in medical devices and implants. This progress was primarily driven by issues of biocompatibility and demands for enhanced mechanical performance of permanent and non-permanent implants as well as medical devices and artificial organs. In the 21st century, the biomaterials community aims to develop advanced medical devices and implants, to establish techniques to meet these requirements, and to facilitate the treatment of older as well as younger patient cohorts. The major advances in the last 10 years from a cellular and molecular knowledge point of view provided the scientific foundation for the development of third-generation biomaterials. With the introduction of new concepts in molecular biology in the 2000s and specifically advances in genomics and proteomics, a differentiated understanding of biocompatibility slowly evolved. These cell biological discoveries significantly affected the way of biomaterials design and use. At the same time both clinical demands and patient expectations continued to grow. Therefore, the development of cutting-edge treatment strategies that alleviate or at least delay the need of implants could open up new vistas. This represents the main challenge for the biomaterials community in the 21st century. As a result, the present decade has seen the emergence of the fourth generation of biomaterials, the so-called smart or biomimetic materials. A key challenge in designing smart biomaterials is to capture the degree of complexity needed to mimic the extracellular matrix (ECM) of natural tissue. We are still a long way from recreating the molecular architecture of the ECM one to one and the dynamic mechanisms by which information is revealed in the ECM proteins in response to challenges within the host environment. This special issue on smart biomaterials lists a large number of excellent review articles which core is to present and discuss the basic sciences on the topic of smart biomaterials. On the other hand, the purpose of our review is to assess state of the art and future perspectives of the so called “smart biomaterials” from a translational science and specifically clinical point of view. Our aim is to filter out and discuss which biomedical advances and innovations help us to achieve the objective to translate smart biomaterials from bench to bedside. The authors predict that analyzing the field of smart biomaterials from a clinical point of view, looking back 50 years from now, it will show that this is our heritage in the 21st century.