Site specific drug delivery systems (DDS) are usually developed to overcome the side effects of conventional ones (e.g. injections or oral ingestions), creating smart drug delivery vehicles characterized with greater efficiency, safety, predictable therapeutic response as well as controlled and prolonged drug release periods. DDS made of hyaluronic acid (HA) and poly-L-lysine (PLL) are promising candidates in the field of local drug delivery due to their high biocompatibility. Moreover, electrostatic attractions between negatively charged HA and positively charged PLL can be used to fabricate multilayer films, bilayer films and hydrogels, avoiding the application of toxic crosslinking agents. In this review, we report the preparation of HA/PLL composites exploiting their intrinsic properties, as well as developed composite application possibilities as controlled drug delivery systems in bone tissue, central nervous system and gene engineering.