Many types of cancer recruit neutrophils that could have protumor or antitumor effects on tumor development. Numerous findings in murine models suggest a predominantly protumoral role for neutrophils in cancer development. However, there are fundamental differences between mouse and human tumors in the evolution of tumors, genetic diversity, immune response, and also in the intrinsic biology of neutrophils that might have a profound impact on tumor development and the function of these cells. A crucial difference is that the majority of mouse tumor models lack the prolonged initial phases of multistage tumor evolution present in humans when antitumoral mechanisms are activated. In this review, we discuss the challenges specific to cross-species extrapolation of neutrophil function during mouse versus human tumor development.