Blood contact biomaterials need to fulfill a strict set of rules to be implanted and used within the human body. In the present chapter, we briefly describe the basic tissue responses upon the implantation of biomaterials, focusing on the interactions established at the surface of the polymer–blood interface and within the surrounding biological environment. Hemocompatibility assessment methods such as thrombosis, coagulation, partial thromboplastin time (PTT), platelet adhesion and aggregation, or hemolysis assays are discussed, together with a description of their principles. In addition, an overview of the ongoing hemocompatibility investigations on natural- and synthetic-based hydrogels is provided. Special attention is given to the intrinsic anti-thrombogenic properties of synthetic hydrogels based on poly(2-hydroxyethyl methacrylate), poly(ethylene glycol) and zwitterionic polymers, while natural hydrogels are discussed as inherent biomaterials or as tools to improve the hemocompatibility of other biomaterials via surface modification strategies. Overall, the importance of hemocompatibility assessment, even as preliminary investigations, is directly shown to be a requirement, in general, for implantable biomaterials and, in particular, for injectable hydrogels targeting blood-contacting applications.