Thalidomide has recently shown considerable promise in the treatment of a number 
of conditions, such as leprosy and cancer. Its effectiveness in the clinic has 
been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell 
costimulatory and antiangiogenic activity. Novel compounds with improved 
immunomodulatory activity and side effect profiles are also being evaluated. 
These include selective cytokine inhibitory drugs (SelCIDs), with greatly 
improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that 
are structural analogs of thalidomide, with improved properties. A third group 
recently identified within the SelCID group, with phosphodiesterase type 
4-independent activity, is in the process of being characterized in laboratory 
studies. This review describes the emerging immunological properties of 
thalidomide, from a historical context to present-day clinical applications, 
most notably in multiple myeloma but also in other cancers, inflammatory 
disease, and HIV. We also describe the laboratory studies that have led to the 
characterization and development of SelCIDs and IMiDs into potentially 
clinically relevant drugs. Early trial data suggest that these novel 
immunomodulatory compounds may supercede thalidomide to become established 
therapies, particularly in certain cancers. Further evidence is required, 
however, to correlate the clinical efficacy of these compounds with their known 
immunomodulatory, antiangiogenic, and antitumor properties.