Cells, the basic units of life, have striking differences at transcriptomic, proteomic and epigenomic levels across tissues, organs, organ systems and organisms. The coordination of individual immune cells is essential for the generation of effective immune responses to pathogens while immune tolerance is maintained to protect the host. In rheumatic diseases, when immune responses are dysregulated, pathologically important cells might represent only a small fraction of the immune system. Interrogation of the contributions of individual immune cells to pathogenesis and disease progression should therefore reveal important insights into the complicated aetiology of rheumatic diseases. Technological advances are enabling the high-dimensional dissection of single cells at multiple omics levels, which could facilitate the identification of dysregulated molecular mechanisms in patients with rheumatic diseases and the discovery of new therapeutic targets and biomarkers. The single-cell technologies that have been developed over the past decade and the experimental platforms that enable multi-omics integrative analyses have already made inroads into immunology-related fields of study and have potential for use in rheumatology. Layers of omics data derived from single cells are likely to fundamentally change our understanding of the molecular pathways that underpin the pathogenesis of rheumatic diseases.