Systemic lupus erythematosus (SLE) poses significant diagnostic challenges. First, it is characterized by a highly variable combination of autoantibodies and a wide range of possible organ involvement and symptoms. Second, no single laboratory test can definitively confirm or exclude the diagnosis. Third, due to the low incidence of SLE, clinicians must carefully balance considering SLE as a potential diagnosis against more common causes of similar symptoms. The joint European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria provide a helpful framework for thinking about SLE diagnosis, although they are not intended for diagnostic use. Nevertheless, several elements of the criteria-such as the requirement for anti-nuclear antibodies (ANA) positivity as an entry point (similar to a screening test), the weighted scoring of clinical and immunological features, and the attribution of findings to SLE only when no more likely alternative explanation exists-highlight principles that are also useful in the diagnostic process. Conceptionally, diagnosing SLE can be seen as a three-step process: (1) considering the possibility of SLE; (2) systematically collecting evidence for or against the diagnosis; and (3) making a diagnostic decision based on whether the accumulated evidence sufficiently supports or refutes the diagnosis. This review follows the three-step framework in discussing the clinical diagnosis of SLE clinical diagnosis.