Abstract: The present invention relates to a high affinity, VNAR polypeptide cross reactive with primate transferrin receptors (“TfR”). This TfR-specific VNAR polypeptide was obtained by screening semisynthetic VNAR phage display libraries against recombinant human TfR-1. The VNAR polypeptides of the invention can be used alone or as a component in conjugates that target the transferrin/transferrin receptor transport system. The invention further includes use of this VNAR, its conjugates and other derivatives in diagnostic and therapeutic methods, e.g., to diagnose, treat and/or prevent a pathological condition, disorder or disease in which it is beneficial to deliver a heterologous biomolecule across the blood brain barrier or other membrane systems. This TfR-specific VNAR polypeptide can also be used to target other biological barriers such the intestines, the placenta or aberrant cells overexpressing TfR-1, for therapeutic benefit in treatment of certain cancer cells and tumors of various tissue types.