Therapy of systemic lupus erythematosus has been facing the paradox of an overwhelming rate of trials testing novel potential therapeutic agents and the lack of US FDA approval of a single new drug for over five decades. Heterogeneity in disease phenotype, concomitant immunosuppressive medication and a lack of unequivocal hard end points for clinical trials have proven to be significant obstacles in establishing efficacy of candidate therapies. Nevertheless, combination regimens with already existing agents have shown efficacy with acceptable safety profiles, mainly in cases of refractory to conventional treatment disease. At the same time, positive results from trials with belimumab, an antibody that targets B cells, opened the way for approval of this agent for the treatment of lupus and lends hope for a new era in systemic lupus erythematosus therapeutics. Here, we review the latest advances in systemic lupus erythematosus therapy, focusing on the balance between efficacy and safety for combination therapeutic regimens and biologics under development.