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Whereas antimalarials have been in use to treat rheumatic disease for over 50 years, their exact mechanism of action remains unclear. Over the past decade, new theories have been proposed in this regard both for rheumatic disease, as well as related conditions.Whereas the classical explanation was an impairment of phago/lysosomal function, antimalarials also appear to have an impact through inhibition of intracellular toll-like receptors (TLRs), particularly TLR9. This may mediate its effect on lupus, rheumatoid arthritis, as well as ancillary conditions including diabetes and hyperlipidemia. The potential role for antimalarials in antiphospholipid syndrome also appears clearer, with an effect proposed through Annexin5 binding.Despite their established clinical utility, the mode of action for antimalarials remains uncertain despite recent advances and still requires further investigation. By better understanding how antimalarials function, their optimal use in the clinical setting can be ensured.