Here we disclose the response of normal human cells to ZnO nanoparticles under different signaling environments and compare it to the response of cancerous cells. ZnO nanoparticles exhibit a strong preferential ability to kill cancerous T cells (-28-35X) compared to normal cells. Interestingly, the activation state of the cell contributes toward nanoparticle toxicity as resting T cells display a relative resistance while cells stimulated through the T cell receptor and CD28 costimulatory pathway show greater toxicity in direct relation to the level of activation. The novel findings of cell selective toxicity towards potential disease causing cells indicate a potential utility of ZnO nanoparticle in the treatment of cancer and/or autoimmunity.