There is a constant examination of the features that may anticipate or predict the likelihood of the clinical benefit that a patient may experience from a given therapy. This is especially true in the case of novel targeted therapies, as proof-of-principle experimental or pilot analyses are increasingly being embedded into clinical protocols. An unprecedented number of significant developments in the field of epidermal growth factor receptor-targeted therapy have occurred in recent months. This is exemplified by the discovery of activating mutations in the catalytic domain of the epidermal growth factor receptor that increase sensitivity to antiepidermal growth factor receptor small-molecule inhibitors. This review discusses the recent advances and controversies of the different approaches to predict the efficacy of antiepidermal growth factor receptor agents and the effectiveness of the tools that we are using to evaluate and predict the efficacy of epidermal growth factor receptor-targeted drugs and their potential pitfalls.