Abstract: The present invention relates to antibodies and antigen-binding portions thereof that bind to and activate an erythropoietin receptor. The invention also relates to nucleic acid sequences encoding such antibodies and antigen-binding portions. The present invention further relates to methods of activating the endogenous activity of an erythropoietin receptor in a mammal using said antibodies and antigen-binding portions, methods of treatment, as well as pharmaceutical compositions comprising said antibodies and antigen-binding portions. The invention further provides compositions and crystals of an erythropoietin receptor in complex with an anti-erythropoietin receptor antibody. Specifically, the high-resolution structure provides binding sites defined by the structure coordinated determined herein.