With the advent of various protein therapeutics in the field of pharmacy and tissue engineering, a need to develop new systems that would ensure the delivery of proteins to the selected target tissue and their controlled release out there has emerged. For this purpose hydrogels proved to be the optimal choice. They are distinguished by a high water content and, in case the hydrogel network is made of biopolymers, also by biocompatibility and non-toxicity. The aqueous environment within hydrogels efficiently simulates the physiological environment and preserves the native structure of proteins. Protein molecules loaded inside the hydrogel can be released into the surrounding tissue continuously over a long period of time. In general protein release can be modulated by different mechanisms. The key structural features of hydrogels and proteins which to a great extent determine the way in which release takes place are presented briefly. Quantitative criteria to determine which mechanism will have a decisive impact on protein release profile are stated. Each individual mechanism is described in brief and particular attention is paid to affinity-based delivery systems nowadays being of special interest. Based on the literature, the development of a mathematical model for protein release from an affinity-based hydrogel is presented.