Dysregulation of the Human Epidermal growth factor Receptor (HER/ErbB) family is associated with tumorigenesis, however HER4’s role remains unclear. Unlike other HER family members (EGFR, HER2, HER3), HER4 presents four isoforms, with different stability and tissue-specific expression. This thesis examines the role of HER4 in cancer. Given the high frequency of HER4 point mutations in cancers such as cutaneous melanoma (CM) (17.34%) and gastroesophageal (GE) cancers (12.22%), models of these cancers were investigated for HER4/ERBB4 isoform expression and activation upon neuregulin stimulation. Additionally, HER4 was investigated in models of Atypical Teratoid Rhabdoid Tumour due to its potential role in this disease. HER4 expression was low/absent in the majority of cell lines investigated, with neuregulin stimulation being cell line-specific. Tissue microarrays of skin and CM samples were analysed for HER4 expression to assess variances between HER4 expression in in vitro models and patients. HER4 expression was higher in malignant and metastatic CM compared to skin samples. Using computational analyses, potentially oncogenic HER4 mutations in CM and GE cancers were identified. To functionally interrogate their impact in in vitro models, CRISPR/Cas9 methods were employed to insert HER4 mutations into CM cell lines. The successfully developed CRISPR/Cas9 HER4-edited CM cell lines reverted to HER4 WT. However, the analysis of a SKMEL24 CM HER4 CRISPR/Cas9 knockout suggested a potential role of HER4 in CM. Due to the interplay between oestrogen and HER4 in oestrogen receptor positive breast cancer and given the observed tendency for female CM patients to exhibit better outcomes than males, oestrogen stimulation was investigated as a potential mechanism that may influence CM tumour behaviour via the HER4 – GPER – RAR-α/RXR-γ axes. In conclusion, this thesis delivered novel insights into HER4 biology/function, identified a deficiency in availability of appropriate CM and GE HER4 cell line models, and developed a novel CM model to investigate HER4 biology.