The human epidermal growth factor receptor (HER/ErbB) family consists of four members: HER-1 or epidermal growth factor receptor (EGFR), HER-2, HER-3, and HER-4. These receptors play a crucial role in regulating cell development, growth, and tumorigenesis. The HER/ErbB receptors are involved in the genesis and progression of various human malignancies. Hence, monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the HER signaling pathway have been explored and continuously being developed as therapeutic strategies for cancer. Although these targeted therapies appear to improve progression-free survival (PFS) and overall survival rates in cancers, therapeutically they offer a limited clinical benefit due to relapse, resistance, and toxicity incidences. This chapter highlights the HER receptor signaling pathways and their roles in tumorigenesis, current therapeutic targets, and various challenges of anti-HER therapies including tumor resistance and toxicity. The emerging targets, newer classes of drugs, and strategies in cancer treatment are further discussed.