Lupus nephritis is a challenging clinical condition for which current therapies are unsatisfactory with respect to both remission induction and unwanted toxic effects. Despite intervention, the rates of end-stage renal disease seem to be increasing in the USA. Discoveries over the past decade have greatly improved our understanding of immune activation and effector inflammatory pathways in lupus nephritis; however, this increased understanding has not yet translated into the approval of an effective new therapeutic agent. An analysis of the mechanisms of action of novel immunomodulatory drugs in multiple models of murine lupus clearly shows that interacting networks of immune and effector pathways are recruited as the disease progresses. Reversing established disease by targeting a single cell population or inflammatory pathway is, therefore, difficult once long-lived autoreactive lymphocyte populations are present and peripheral organs are inflamed. Data from murine models of lupus suggest that we need to consider new paradigms for the management of systemic lupus erythematosus that include earlier immune intervention, long-term maintenance therapies and protection of target organs.