Isolated antibodies and antigen binding fragments thereof directed against Ovrl 10 which is expressed by head and neck, ovarian, endometrial, kidney, pancreatic, lung or breast cancer are provided. Also provided are cells and methods for their production as well as methods for their use in killing an Ovrl 10-expressing cancer cells and alleviating or treating an Ovrl 10-expressing cancer in a mammal. The anti-Ovrl 10 antibodies modulate Ovrl 10 function or internalize upon binding to Ovrl 10 expressed by mammalian cells in vitro and in vivo. Compositions comprising an anti-Ovrl 10 antibody and a carrier as well as articles of manufacture or kits thereof are also provided. In addition, isolated nucleic acids encoding an anti-Ovrl 10 antibody, expression vectors containing the isolated nucleic acids, and host cells containing the vectors are provided.