Silk fibroin (SF), a naturally occurring protein polymer, has several unique properties making it a favorable matrix for the incorporation and delivery of a range of therapeutic agents. SF is biocompatible, slowly biodegradable, and endowed with excellent mechanical properties and processability. Novel manufacturing techniques including mild all-aqueous processes have expanded its range of application even to sensitive protein and nucleic acid therapeutics. SF matrices were demonstrated to successfully deliver protein drugs and preserve their potency. Adjustments in SF crystallinity, concentration and structure, the design of the delivery systems as well as the molecular weight and structure of the embedded agents represent important variables when it comes to precisely tailor the release kinetics of SF matrices. Other strategies to fine-tune the release from SF matrices comprise the embedment of drug loaded micro- or nanoparticles or the coating of micro- or nanoparticles with SF films. So far, the main focus of SF drug delivery systems has been on tissue regeneration applications. For instance, growth factor loaded SF scaffolds were suggested for the tissue engineering of bone and cartilage, as well as for vascular and nerve regeneration devices and wound healing products. Moreover, SF matrices were proposed for oral, transmucosal and ocular drug delivery. This article reviews SF properties and fabrication processes that affect the release from SF drug delivery systems. For illustration, we discuss a variety of examples for the incorporation of drugs into SF systems and their release.