SLE is a chronic autoimmune disease involving multiple systems. Patients with SLE are highly susceptible to infections due to the combined effects of their immunosuppressive therapy and the abnormalities of the immune system that the disease itself causes, which can increase mortality in these patients. The differentiation of SLE activity and infection in a febrile patient with SLE is extremely difficult. Activity indexes are useful to identify patients with lupus flares but some clinical and biological abnormalities may, however, make it difficult to differentiate flares from infection. Several biological markers are now recognized as potential tools to establish the difference between SLE activity and infection, including CRP and procalcitonin. It is possible, however, that the use of only one biomarker is not sufficient to confirm or discard infection. This means that new scores, which include different biomarkers, might represent a better solution for differentiating these two clinical pictures. This review article describes several markers that are currently used, or have the potential, to differentiate infection from SLE flares.