Rheumatic diseases have complex aetiologies that are not fully understood, which makes the study of pathogenic mechanisms in these diseases a challenge for researchers. Next-generation sequencing (NGS) and related omics technologies, such as transcriptomics, epigenomics and genomics, provide an unprecedented genome-wide view of gene expression, environmentally responsive epigenetic changes and genetic variation. The integrated application of NGS technologies to samples from carefully phenotyped clinical cohorts of patients has the potential to solve remaining mysteries in the pathogenesis of several rheumatic diseases, to identify new therapeutic targets and to underpin a precision medicine approach to the diagnosis and treatment of rheumatic diseases. This Review provides an overview of the NGS technologies available, showcases important advances in rheumatic disease research already powered by these technologies and highlights NGS approaches that hold particular promise for generating new insights and advancing the field.