Immunomodulatory drugs (IMiDs) are thalidomide analogues, which possess pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. Their development was facilitated by an improved understanding in myeloma (MM) biology and initiated a profound shift in the therapeutic approach towards MM. Despite the diverse effects of IMiDs in vitro, the relative contribution of each effect towards their ultimate anti-MM activity is still unclear. Based on in vitro data, it appears that anti-proliferative effects and downregulation of crucial cytokines are their most important anti-MM attributes. Although the co-stimulatory effects on T and NK cells have been heralded as a unique and important property of IMiDs towards enhancing anti-MM immune activity, these in vitro effects have yet to be firmly corroborated in vivo. Much is yet to be elucidated regarding the complex interplay of immunomodulatory cytokines that occurs in vivo, which ultimately dictates the net effects of IMiDs in MM-the understanding of which is necessary to facilitate optimal manipulation of these drugs in future MM management.