Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by the deposition of autoantibodies and immune complexes, leading to tissue damage. The immunopathogenesis of SLE is like a jigsaw puzzle, some pieces of which are missing or have not fallen into place. In predisposed individuals, the initial stimulus is likely to be one or more of the environmental agents interacting with susceptibility genes. Once the critical threshold is breached there is a failure of the immune system to downregulate the ensuing abnormal immune response, involving polyclonal B cell activation and hyperactive T cell help. Key questions include, what are the processes behind the availability of autoantigens and the breakdown of tolerance that give rise to the pathogenic autoantibodies? Current areas of research also involve the roles played by cytokines, adhesion molecules, co-stimulatory molecules and apoptosis.