Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment.