Distinguishing rheumatic diseases from their mimickers can be a serious challenge in clinical practice, and rheumatologists as well as other related medical specialties are facing it in their everyday clinical practice. Symptoms such as joint pain, swelling and stiffness are not exclusive to rheumatic diseases and may result from other autoimmune disorders, infections, malignancies, metabolic disorders or degenerative conditions. Furthermore, misinterpreting serologic tests, such as rheumatoid factor and antinuclear antibodies, without a clear clinical correlation between them, can lead to diagnostic errors. On the other hand, infections, malignancy-associated syndromes, drug-induced conditions and non-inflammatory pain syndromes like fibromyalgia can all mimic the clinical picture of rheumatic diseases, complicating the diagnosis even more. Overlooking systemic involvement in conditions like systemic lupus erythematosus or vasculitis may result in misdiagnosis as psychiatric or functional disorders, delaying appropriate diagnosis. A sound strategy stands in maintaining a broad differential diagnosis, careful interpretation of serologic and imaging results and a thorough clinical history including current drugs. By adopting a systematic and comprehensive diagnostic approach, a rheumatologist can be more confident in order to differentiate a rheumatic disease from its mimicker, avoiding inappropriate treatments.