Soluble recombinant CD44 hyaluronic acid binding domain (CD44HABD) inhibits angiogenesis in vivo in chick and mouse and thereby inhibits human tumor growth of various origins. The anti-angiogenic effect of CD44-HABD is independent of hyaluronic acid (HA) binding, since non-HA-binding mutants of CD44HABD still maintain anti-angiogenic properties. The invention discloses soluble non glycosylated CD44 recombinant proteins as a novel class of angiogenesis inhibitors based on targeting of vascular cell surface receptor. A method of block of angiogenesis and treatment of human tumors using recombinant CD44 proteins as well as their analogues is disclosed. As a further embodiment of the invention, methods for screening for new drug targets using CD44 recombinant proteins and their analogues are presented.