Heat shock protein (HSP) 90 regulates client oncoprotein maturation. The chaperone function of HSP90 is blocked by 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), although it results in transcription and translation of antiapoptotic HSP proteins. Using three myeloma cell lines, we tested whether inhibition of transcription/translation of HSP or client proteins will enhance 17-AAG-mediated cytotoxicity. 8-Chloro-adenosine (8-Cl-Ado), currently in clinical trials, inhibits bioenergy production, mRNA transcription, and protein translation and was combined with 17-AAG. 17-AAG treatment resulted in HSP transcript and protein level elevation. In the combination, 8-Cl-Ado did not abrogate HSP mRNA and protein induction. HSP90 requires ATP to stabilize client proteins; hence, expression of signal transducer and activator of transcription 3 (STAT3), Raf-1, and Akt was analyzed. 17-AAG alone resulted in <10% change in STAT3, Raf-1, and Akt protein levels, whereas no change was observed for 4E-BP1. In contrast, the combination treatment resulted in a >50% decrease in client protein levels and marked hypophosphorylation of 4E-BP1. 8-Cl-Ado alone resulted in a <30% decrease of client proteins and 4E-BP1 hypophosphorylation. 8-Cl-Ado combined with 17-AAG resulted in more than additive cytotoxicity. In conclusion, 8-Cl-Ado, which targets transcription, translation, and cellular bioenergy, enhanced 17-AAG-mediated cytotoxicity in myeloma cells.