The interferon gene signature (IGS) is derived from the expression of interferon-regulated genes and is classically increased in response to type I interferon exposure. A raised whole blood IGS has increasingly been reported in rheumatic diseases as sequencing technology has advanced. Although its role remains unclear, we explore how a raised IGS can function as a clinically relevant biomarker, independent of whether it is a bystander effect or a key pathological process. For example, a raised IGS can act as a diagnostic biomarker when predicting rheumatoid arthritis in patients with arthralgia and anti-citrullinated protein antibodies, or predicting systemic lupus erythematous (SLE) in those with antinuclear antibodies; a theragnostic biomarker when predicting response for patients receiving disease modifying therapy, such as rituximab in rheumatoid arthritis; a biomarker of disease activity (early rheumatoid arthritis, dermatomyositis, systemic sclerosis, SLE); or finally a predictor of clinical characteristics, such as lupus nephritis in SLE or disease burden in primary Sjögren's syndrome. A high IGS does not uniformly predict worse clinical phenotypes across all diseases, as demonstrated by a reduced disease burden in primary Sjögren's syndrome, nor does it predict a universally poorer response to all therapies, as shown in rheumatoid arthritis. This dichotomy highlights both the complexity of type I interferon signalling in vivo and the current lack of standardisation when calculating the IGS. The IGS as a biomarker warrants further exploration, with beneficial clinical applications anticipated in multiple rheumatic diseases.