Studies have begun to emerge showing critical roles for neutrophils in tumorigenesis. Neutrophils can have a significant impact on the tumor microenvironment via their production of cytokines and chemokines, which influence inflammatory cell recruitment and activation. Additionally, products secreted from neutrophils, such as reactive oxygen species and proteinases, have defined and specific roles in regulating tumor cell proliferation, angiogenesis, and metastasis. Although evidence suggests that neutrophils act in a decidedly protumor capacity in vivo, recent studies indicate that neutrophils may be manipulated to exhibit cytotoxicity against tumors. Herein, we explore the idea of targeting tumor-associated neutrophils as a means of antitumor therapy and the important ramifications such manipulation could pose to host tissues. Cancer Res; 71(7); 2411–6. ©2011 AACR.