Over the past 50 years, thalidomide has been a target of active investigation in 
both malignant and inflammatory conditions. Although initially developed for its 
sedative properties, decades of investigation have identified a multitude of 
biological effects that led to its classification as an immunomodulatory drug 
(IMiD). In addition to suppression of tumor necrosis factor-alpha (TNF-alpha), 
thalidomide effects the generation and elaboration of a cascade of 
pro-inflammatory cytokines that activate cytotoxic T-cells even in the absence 
of co-stimulatory signals. Furthermore, vascular endothelial growth factor 
(VEGF) and beta fibroblast growth factor (bFGF) secretion and cellular response 
are suppressed by thalidomide, thus antagonizing neoangiogenesis and altering 
the bone marrow stromal microenvironment in hematologic malignancies. The 
thalidomide analogs, lenalidomide (CC-5013; Revlimid) and CC-4047 (Actimid), 
have enhanced potency as inhibitors of TNF-alpha and other inflammatory 
cytokines, as well as greater capacity to promote T-cell activation and suppress 
angiogenesis. Both thalidomide and lenalidomide are effective in the treatment 
of multiple myeloma and myelodysplastic syndromes for which the Food and Drug 
Administration granted recent approval. Nonetheless, each of these IMiDs remains 
the subject of active investigation in solid tumors, hematologic malignancies, 
and other inflammatory conditions. This review will explore the pharmacokinetic 
and biologic effects of thalidomide and its progeny compounds.