A popular approach to attaining controlled drug delivery from polymer based systems involves the use of cross-linkers. In order to improve the properties of polymers specific to their applications, they can be modified by either physical cross-linkers (high pressure, irradiation) or chemical cross-linkers (glutaraldehyde, genipin). This chapter provides an insight into the different types and mechanisms of cross-linking. It reviews the existing drug delivery systems to understand the effects of cross-linking in them. The recent applications of cross-linked polymeric drug delivery and tissue engineering systems are also discussed.