Polyarthritis comprises a large number of conditions ranging from rheumatoid arthritis (RA) to metabolic conditions such as ochronosis. Differential diagnosis begins with delineation of inflammatory from non-inflammatory disorders using laboratory markers of inflammation. The latter are good but they can be misleading. Laboratory tests help in the diagnosis of rheumatic diseases as well as their prognostication. The choice of serological tests should be based on clinical differential diagnosis and not 'arthritis panels'. The point of time when the test is performed in the clinical course of disease can have an important influence on the result obtained. Anti-citrullinated protein antibody (ACPA), rheumatoid factor, human leucocyte antigen (HLA) B27 and imaging are routinely employed for the early diagnosis of RA and spondyloarthritis (SpA). Despite advances in musculoskeletal imaging modalities such as ultrasonography (USG) with power Doppler, conventional as well as extremity magnetic resonance imaging (MRI) and dual-energy computed tomography (DECT), their exact place in clinical rheumatology remains to be defined. Synovial fluid examination has only a limited role in the investigations of new-onset polyarthritis.