Androgen withdrawal therapy (AWT) remains the cornerstone of advanced prostate cancer (PCa) therapy; however, patients on this therapy eventually relapse, caused by the advent of castration-resistant PCa. This stimulates investigation into additional therapeutic targets that may delay or impede the development of CRPC. The EGFR family of receptor tyrosine kinases is intimately involved in prostate cancer (PCa) development. EGFR/ErbB1 and HER2/ErbB2 have been clinical targets in androgen-dependent PCa but targeting each individually encourages compensatory signaling by a third member, HER3/ErbB3. Activated HER3/ErbB3 contributes to the onset of castrate-resistant PCa (CRPC), presently an incurable condition. We previously showed that dual EGFR/HER2 inhibition sensitizes PCa cells to androgen withdrawal by suppressing ErbB3 (Clin Cancer Res. 2011 Oct 1;17(19):6218–28). Based on these results, we hypothesized that the dual EGFR/HER2 inhibitor lapatinib (‘Tykerb’, Lap) may sensitize PCa cells to AWT. Athymic nu/nu mice were subcutaneously implanted with CWR22 (androgen-dependent) or CWR22Rv1 (CRPC) tumors derived from human prostate tumors. Tumor-bearing mice were either castrated or left intact, and were treated with the FDA-approved, reversible, dual-kinase, small-molecule inhibitor lapatinib or vehicle alone. Castration prevented tumor growth in CWR22 tumor-bearing mice, both those treated with lapatinib or vehicle, but in intact mice, lapatinib actually stimulated tumor growth. In CWR22Rv1 tumor-bearing mice, lapatinib was ineffective, both in intact or castrated animals. Therefore we further investigated the effect of dual EGFR/ErbB2 inhibitors in PCa. Comparison of various cells showed that lapatinib was effective in LNCaP cells and its CRPC derivatives, but was ineffective in other lines, including PC-346C cells which express a wild-type androgen receptor (AR), whereas LNCaP cells and its derivatives express a mutant AR (T877A). In the latter cell line, lapatinib increased cell growth similar to that seen in CWR22 tumors. Hence, we investigated the effect of other dual EGFR/HER2 inhibitors in PCa cells. In contrast to lapatinib, dacomitinib (PF00299804, Pfizer, PF), an irreversible, small-molecule, dual-kinase inhibitor currently in several clinical trials for a variety of tumors, was more effective and completely inhibited cell growth in the majority of cell lines. When combined, PF and Lap decreased tumor cell viability, increased cell cycle arrest, increased apoptosis, and downregulated ErbB3 protein. These preclinical data support the hypothesis that dual-kinase inhibition may be a viable therapeutic strategy. They also indicate that prostate cancer patients must be carefully preselected, based on their tumor type, and offered personalized therapeutic regimens in order to ensure maximum efficacy of dual-kinase inhibitory treatment.