Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully de®ned. In the present study, gene expression pro®les of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression pro®les of Dex-sensitive and Dex-resistant MM cells and identi®ed a number of genes which may confer Dexresistance. Finally, gene pro®ling of freshly isolated MM patient cells validates our in vitro MM cell line data, con®rming an in vivo relevance of these studies. Collectively, these ®ndings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival.