Affinity-based release systems use transient interactions to sustain and control the release of a therapeutic from a polymeric matrix. The most common affinity-based systems use heparin-based scaffolds to sustain the release of heparin-binding proteins, such as fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). However, novel affinity-based systems based on, for example, protein-protein or DNA-protein interactions, are emerging to control the release of an expanding repertoire of therapeutics. Mathematical models of affinity-based systems have provided a thorough understanding of which parameters affect release rate from these systems, and how these release rates can be tuned. In this review, recent affinity-based release systems will be described, including an overview of the various types of affinity interactions used to modulate release, the mechanisms by which release from these systems is tuned, and the time scales of sustained release. This advanced drug delivery paradigm provides tunable and predictable release rates and has expanded the scope of deliverable therapeutics for tissue repair and regeneration.