Fibrin, derived from key proteins involved in blood clotting (fibrinogen and thrombin), is a self-assembling biopolymer. The range of clinical applications and types of procedure that incorporate fibrin sealants is expanding. While fibrin sealants have been initially used for their hemostasis and tissue sealing properties, they have also been recently used as a successful platform in various tissue regeneration applications necessitating cell and/or growth factor delivery. One of the primary reasons for this success is that fibrin provides a biocompatible physical structure and many of the important biological properties needed for successful tissue regeneration. In addition, these inherent biological properties can be enhanced by combining fibrin with other biomaterials (hence improving the overall biological and/or mechanical properties of the composite matrix) or by incorporating bioactive molecules to control cell proliferation, migration, or differentiation during tissue regeneration. This chapter summarizes key aspects of the composition, structure, as well as mechanical, fibrinolytic, and biological properties of fibrin as these characteristics influence its efficacy and performance. Applications of fibrin and fibrin-based biomaterials in tissue engineering and in clinical practice are also highlighted, with an emphasis on the use of fibrin as a delivery system for cells and bioactive molecules.