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Therapeutic advances have improved cancer survival outcomes for an increasing number of patients, but novel approaches are still urgently needed for patients who cannot tolerate, or do not respond to current treatments. Erythropoietin-producing hepatocellular receptor A2 (EphA2) is highly expressed in a variety of solid tumors, which is associated with poor prognosis, especially in tumors considered difficult-to-treat, such as pancreatic and head and neck cancer. EphA2 has emerged as a promising therapeutic target for the treatment of solid tumors; however, efficacy and safety issues have halted clinical development of previous EphA2-targeting agents including MEDI-547, DS-8895a, MM-310, and dasatinib. Despite these setbacks, interest in targeting EphA2 in solid tumors remains, with ongoing development of investigational therapies such as antibodies, antibody drug conjugates, EphA2 antagonists, peptide drug conjugates, bicyclic peptide drug conjugates, and tyrosine kinase inhibitors. Among these, BT5528, a Bicycle® Drug Conjugate (BDC), has shown an emerging differentiated safety profile, in contrast to prior EphA2-targeting agents, and promising antitumor activity in patients with advanced solid tumors. BT5528 comprises an EphA2-targeting bicyclic (Bicycle) peptide, linked to the cytotoxin monomethyl auristatin E (MMAE) via a valine-citrulline cleavable linker. The high specificity of BT5528 to EphA2, combined with its high affinity, enables precision-guided delivery of MMAE, while its peptidic nature results in rapid distribution and retention of MMAE within the tumor, limited systemic exposure, and liver-sparing renal elimination. The preclinical and emerging clinical data for BT5528 suggest that novel approaches to targeting EphA2 can achieve efficacy without the safety issues that plagued earlier agents. Here, we review EphA2 as a target and the historical and current clinical development of EphA2-targeting therapeutic agents.