Targeting members of the human epidermal growth factor receptor family, especially EGFR and HER2, has been an established strategy for the treatment of tumors with abnormally activated receptors due to overexpression, mutation, ligand-dependent receptor dimerization and ligand-independent activation. Less attention has been paid to the oncogenic activity of HER3, although there is growing evidence that it mediates resistance to EGFR and HER2 pathway directed therapies. The main caveat for the development of effective HER3 targeted therapies is the absence of a strong enzymatic activity to target, as well as the limited potential for single-agent activity. In this review, we highlight the role of HER3 in cancer and, more specifically, in lung cancer. The basis for HER3 involvement in HER2 resistance and EGFR inhibition is discussed, as well as current pharmacologic strategies to combat HER3 inhibition.