Small animal models have given great insight into tumor biology, but have been less successful at predicting clinical outcome. It is expected that newer models will be more predictive because they are better tumor mimics. Unfortunately, other impediments to clinical prediction remain, as reviewed in this chapter. Given these limits, plus advances in other approaches, how can small animal models best be exploited for developing new tumor therapies? Suggestions include focus on targets that are shared by many different tumors, and use of small animal models to reveal broad principles or answer specific questions, rather than aiming for rodent cures.