Natural killer (NK) cell immunosurveillance may be impaired by malignant disease, resulting in tumor escape and disease progression. Therapies that enhance NK cytotoxicity may therefore prove valuable in remission-induction and maintenance treatment regimens. Acute lymphoblastic leukemia (ALL) has previously been considered resistant to NK cell lysis and not tractable to this approach. Our study demonstrates that bortezomib, valproate and troglitazone can up-regulate NK activating ligands on a B-ALL cell line and on a proportion but not all adult primary B-ALL samples. Drug-treated ALL cells trigger higher levels of NK degranulation, as measured by CD107a expression, and this effect is dependent on signaling through the NK activating receptor NKG2D. These results suggest that bortezomib, valproate and troglitazone may have clinical utility in sensitizing ALL to NK mediated lysis in vivo.