Poly[N-(2-hydroxypropyl) methacrylamide] (HPMA) was one of the first polymers applied as polymer drug conjugate in the clinics. Since then many attempts have been made to expand the functionality of HPMA-based copolymers from advanced synthetic pathways to multiple biomedical applications. This Feature Article highlights multifunctional HPMA based copolymers prepared by controlled radical polymerization and subsequent post-polymerization modification of activated ester precursor polymers via aminolysis. This approach combines precise control of the polymer's microstructure (molecular weight, dispersity, block copolymer formation, end group functionalization) with an easy introduction of various multifunctional groups. The obtained polymers can be used as versatile targeted drug carriers for sophisticated molecular imaging techniques that provide detailed information about structure property relationships both in vitro as well as in vivo. Moreover, recent studies have shown that such multifunctional HPMA copolymers may have high potential as advanced carriers in the field of tumor immunotherapy.