Cancer cells re-configure their glycosaminoglycan (GAG) composition to promote cell proliferation, migration, and invasion. Distinct cancer-specific GAGs are candidate targets for therapy, but GAG targeting is challenging due to lack of specific binding technologies. We have developed a cancer-specific GAG targeting technology based on evolutionarily refined lectin’s from the malaria parasite Plasmodium falciparum. As an integrated part of their pathological lifecycle, malaria parasites express VAR2CSA proteins on the surface of infected erythrocytes, mediating specific attachment to distinct chondroitin sulfate (CS) GAG modifications in the human placenta. The malignant and placental tissue compartments display a common oncofetal CS pattern, which can be specifically targeted by recombinant malarial VAR2CSA (rVAR2) proteins. In most cancers, oncofetal CS is redundantly conjugated to a limited repertoire of proteoglycans differentially expressed on the cell surface and in the microenvironment. Accordingly, rVAR2 proteins can be employed in diagnostic and therapeutic applications to detect and target various types of human cancer. Our work exemplifies how evolutionarily refined parasite host-anchor molecules can be conveniently exploited to target specific cancer-associated GAG chains.