ErbB3 receptors are unique members of the erbB receptor tyrosine kinases (RTKs), which are often aberrantly expressed and/or activated in human cancers. Unlike other members in the family, erbB3 lacks or has impaired kinase activity. To transduce cell signaling, erbB3 has to interact with other RTKs and to be phosphorylated by its interactive partners, of those, erbB2 is the most important one. ErbB3 is frequently co-expressed with other RTKs in cancer cells to activate oncogenic signaling, such as phosphoinositide-3-kinase/protein kinase B (Akt) pathway, mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway, Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway, etc. and thereby promote tumorigenesis. Numerous studies have demonstrated that activation of erbB3 signaling plays an important role in the progression of a variety of tumor types, such as erbB2-overexpressing breast cancer, castration-resistant prostate cancer, platinum refractory/resistant ovarian cancer, epidermal growth factor receptor TKI-resistant non-small-cell lung cancer, and others. Basic research on the underlying mechanisms implicated the functions of erbB3 as a major cause of treatment failure in cancer therapy. Thus, concomitant inhibition of erbB3 is thought to be required to overcome the resistance and to effectively treat human cancers. This review focuses on the latest advances in our understanding of erbB3-initiated signaling in the development of resistance to cancer treatments.