Infections remain one of the leading causes of death in systemic lupus erythematosus (SLE), despite awareness of factors contributing to increased susceptibility to infectious diseases in SLE. Clinicians report challenges and barriers when encountering infection in SLE as certain infections may mimic a lupus flare. There are no evidence-based practice guidelines in the management of fever in SLE, with suboptimal implementations of evidence-based benefits related to infectious disease control and/or prevention strategies in SLE. Vigilance in identifying an opportunistic infection must be stressed when confronted by a diagnostic challenge during a presentation with a febrile illness in SLE. A balanced approach must focus on management of infections in SLE, and reduction in the glucocorticoids dose, given the need to control lupus disease activity to avoid lupus related organ damage and mortality. Clinical judgement and application of biomarkers of lupus flares could reduce false positives and overdiagnosis and improve differentiation of infections from lupus flares. Further precision-based risk and screening measures must identify individuals who would benefit most from low dose immunosuppressive therapy, targeted immune therapy, and vaccination programs.