EphA2 is a receptor tyrosine kinase that is overexpressed by many human cancers, and is often associated with poor prognostic features. It is involved in many processes crucial to malignant progression, such as migration, invasion, metastasis, proliferation, survival and angiogenesis. Inducing EphA2 downregulation by any one of several mechanisms (antibody-mediated inhibition of signalling, antibody-mediated downregulation of total EphA2 expression and siRNA-mediated inhibition of expression) has been shown to decrease tumour growth, prolong survival and inhibit angiogenesis in multiple preclinical models of ovarian, breast and pancreatic cancer. Targeting EphA2 is especially attractive in ovarian cancer, in which overexpression is present in > 75% of cases. This disease is highly responsive to chemotherapy, and EphA2 inhibition is especially effective in combination with taxanes. This demonstrated efficacy, along with the low expression of EphA2 by normal adult tissues and lack of demonstrable toxicities in preclinical models, suggest that long-term treatment with EphA2-targeting agents is an attractive approach for ovarian cancer therapy.