The revival of thalidomide began shortly after the drug was withdrawn from the 
market because of its teratogenic properties. Therapeutic effects of thalidomide 
were found accidentally in leprosy patients with erythema nodosum leprosum 
(ENL). Subsequent research widened the understanding of the activity of 
thalidomide, and with improved methodology and the augmented background 
knowledge of immunology it was possible to interpret the properties of 
thalidomide more coherently. Effects on tumour necrosis factor-alpha (TNFalpha) 
release play an important role in the ability of thalidomide to affect the 
immune system. Alteration of synthesis and release of cytokines such as 
interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-gamma is 
involved in the complex mechanisms of thalidomide. Thalidomide targets 
leucocytes, endothelial cells and keratinocytes, affecting them in a different 
manner and at different cellular levels. Changes in the density of adhesion 
molecules alter leucocyte extravasation and the inflammatory response in the 
tissue involved. Several mechanisms for the teratogenic action of thalidomide 
are currently under review, but this mode of action of the drug still remains 
unclear and we review evidence-based hypotheses for the teratogenicity of 
thalidomide. Thalidomide shows significant clinical impact in several diseases 
such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic 
lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting 
syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and 
some solid tumours. In 1998 the US Food and Drug Administration approved 
thalidomide exclusively for the treatment of ENL, and strict conditions were 
stipulated for its use in order to prevent teratogenic adverse effects. However, 
despite the promising findings of thalidomide at the molecular level, namely its 
anti-TNFalpha properties and its intercalation with DNA, and activity in 
clinical trials, there is still a great need for more intensive research.