Type I interferons (IFN) are a class of inducible and protective cytokines best known for immune defence against viruses and intracellular bacteria. Inappropriate stimulation or defective negative regulation of type I IFN expression however can lead to persistent type I IFN activity with detrimental effects. This is particularly relevant for a class of monogenic autoinflammatory diseases ("type I interferonopathies"), along with many other complex rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), systemic sclerosis (SSc), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). Direct detection of type I interferon protein in biologic samples has proved challenging, thus indirect methods are often used to infer the presence of type I IFN via quantification of antiviral activity and/or induced expression of IFN-responsive genes. While some of these methods have been used to inform clinical care, none have proven feasible for everyday clinical practice. However, with new technologies emerging, this may soon change. This review provides a brief summary of the available methods to gauge the presence of type I IFN and their application for the improved understanding, diagnosis and monitoring of type I interferonopathies and other rheumatic diseases.