There is considerable evidence that epidermal growth factor receptor (EGFR) plays an important role in non-small-cell lung cancer tumor growth and proliferation. Clinical experience with EGFR inhibitors, such as erlotinib, gefitinib, and cetuximab, has suggested that there are subgroups of patients with non-small-cell lung cancer that demonstrate dramatic responses to these agents. Researchers have sought to determine whether molecular or clinical characteristics correlate with therapeutic outcomes. Rash, the most commonly reported adverse effect of anti-EGFR therapy, has also been examined as a potential marker of response. Several trials evaluating anti-EGFR therapies have reported a positive correlation between rash and response and even rash and survival. If rash is truly a predictor of outcome, it becomes imperative that clinicians identify effective methods for managing this toxicity to avoid unwanted dose reduction, therapy interruption, delay, or discontinuation in patients experiencing a therapeutic benefit. Unfortunately, because of a lack of well-defined rash etiology, variability of use, and interpretation of rash grading scales, as well as a lack of clinical trials evaluating approaches to rash management, we are left without systematic, evidence-based guidelines for treatment. Preliminary results of a prospective study evaluating a rash treatment algorithm developed at the University of Texas M. D. Anderson Cancer Center have been positive, and there is universal agreement that initiation of more prospective trials to evaluate EGFR-inhibitor rash management is needed.