Recent developments in the immuno-oncology field strongly support a role for the immune system in both the prevention and progression of melanoma. Melanoma is a highly immunogenic cancer, including its ability to induce tumour antigen-specific B cell and antibody responses through largely unknown mechanisms. This review considers likely hypothetical mechanisms by which anti-tumour surveillance detects pre-cancerous cells and by which immune (including B cell and antibody) responses may be elicited during malignancy. The review further considers potential pro- and anti-tumour functions of B cells and antibodies (including tertiary lymphoid structures) in both the tumour microenvironment and in circulation. Although the vast majority of studies have focused on T cells, recent evidence highlights the important roles of B cells in response to malignancy. B cells and antibodies are also discussed in the context of their potential utility as clinical biomarkers for various applications (as diagnostic, prognostic, therapeutic efficacy, and toxicity proxies), with a particular focus on protein microarray-based antibody detection and quantitation. Although the role of B cells in melanoma is incompletely understood, the measurement of circulating tumour-specific antibodies represents a promising avenue in the search for melanoma-relevant biomarkers.