Infection is generally followed by inflammation; uncontrolled inflammation often precedes multiple organ failure and cancer. In this review, recent developments on the potential use of siRNAs in the treatment of inflammatory diseases of the liver, lung, joints and colon are summarized. Although target identification and a high degree of efficacy of siRNA have been achieved in cell culture studies in vitro, the major challenge has been the identification of acceptable delivery systems for in vivo application. In addition to delivery challenges, off-target effects and interferon response are major hurdles to overcome before a suitable siRNA formulation can be developed as a therapeutic. Nevertheless, recent preclinical and clinical studies have demonstrated promise in the treatment of diseases related to inflammation of the joints, lungs and colon, where delivery of siRNAs can be achieved without systemic administration.