Background <p>Human epidermal growth factor receptor 3 (HER3/ErbB3) is classically recognized as a kinase-impaired member of the epidermal growth factor receptor (EGFR) family, which can initiate oncogenic signaling by heterodimerizing with family members. However, the emerging drug resistance issues of HER-targeted therapies emerges have urged researchers to decipher the role of HER3 as a versatile signaling hub, which is beyond its canonical paradigm.</p> Main body <p>This review delineated the non-canonical landscape of HER3, providing a specialized dissection of its roles which distinguished from the general overviews. We summarized the non-EGFR family heterodimerization partners for HER3 (e.g. MET, FGFR, and IGF1R) and its unique role as a transcriptional co-regulator in the nucleus, and discussed the clinical conundrum regarding its divergent prognostic roles in different cancer types. By integrating the cutting-edge findings in recent years, this review presented the pivotal role of tumor cells hijacking HER3 to achieve metabolic reprogramming and the regulation of tumor microenvironment. These non-canonical mechanisms of HER3 collectively contribute to the adaptive resistance to radiotherapy, chemotherapy, and immunotherapy.</p> Conclusions <p>By integrating current insights and analyzing unresolved paradoxes in published data, this review elaborated the versatile roles of HER3, and constructed a novel theoretical framework to lay foundation for conquering the challenges of therapeutic resistance in precision oncology by developing next-generation HER3-targeted strategies.</p>