Hydrogel scaffolds hold great promise for developing novel treatment strategies in the field of regenerative medicine. Within this context, silk fibroin (SF) has proven to be a versatile material for a wide range of tissue engineering applications owing to its structural and functional properties. In the present review, we report on the design and fabrication of different forms of SF-based scaffolds for tissue regeneration applications, particularly for skin, bone, and neural tissues. In particular, SF hydrogels have emerged as delivery systems for a wide range of bio-actives. Given the growing interest in the field, this review has a primary focus on the fabrication, characterization, and properties of SF hydrogels. We also discuss their potential for the delivery of drugs, stem cells, genes, peptides, and growth factors, including future directions in the field of SF hydrogel scaffolds.