Adjuvant endocrine therapy for breast cancer is associated with significant improvements in disease-related outcomes. Five years of tamoxifen therapy is associated with 41 and 34% reductions in annual breast cancer recurrence and death rate, respectively [1]. Adjuvant aromatase inhibitor (AI) use instead of or in sequence with tamoxifen is slightly superior to single agent tamoxifen in terms of improvement in disease-free survival, but with comparable overall survival benefit [2, 3]. Despite these beneficial outcomes, up to 50% of women discontinue these potentially life-saving medications prior to completion of the recommended 5 years of therapy [4–7]. One of the main reasons for treatment discontinuation is medication-associated side effects that may negatively impact quality of life. Few studies reported to date have compared outcomes and emergence of symptoms in women with early stage breast cancer treated with different AIs. In this issue, Dixon and colleagues report results from a prospective study investigating the effects of two nonsteroidal AIs on patient-reported outcomes using a crossover trial design, in an attempt to elucidate differences in tolerability of AIs by individual patients. The authors randomized 181 postmenopausal women with early stage breast cancer to letrozole for 12 weeks followed immediately by anastrozole for 12 weeks, or the reverse sequence. The primary endpoint, difference in quality of life measures between the two drugs, was evaluated using the validated Functional Assessment of Cancer TherapyBreast (FACT-B)-endocrine subscale (ES) questionnaire. Secondary endpoints included differences between patientreported side effects and medication preference. Consistent with prior reports, the most common adverse events reported by Dixon and colleagues were arthralgias and hot flashes. Importantly, no differences were observed between regimens for adverse events, quality of life, or treatment discontinuation rates. Overall, 11.6% (21/181) of participants discontinued either AI, with 9 withdrawals during the first 12 weeks of therapy (2 on anastrozole and 7 on letrozole), and an additional 10 withdrawals following the transition to the second medication (5 on each AI). Despite the lack of differences in adverse event reporting between letrozole and anastrozole for all study endpoints, about two-thirds of individuals reported a preference for one AI versus the other. Given the substantial improvements in breast cancerrelated outcomes associated with endocrine therapy, minimizing drug-related toxicity and insuring high quality of life for an individual who is receiving the therapy is critical. The study by Dixon et al. confirms reports from prior prospective studies demonstrating that the most common AI-associated toxicity is musculoskeletal, affecting about half of treated patients, and results in early treatment discontinuation in 10–15% of women [8–10]. Although most AI-associated toxicities are believed to be due to a class effect, this study demonstrated that the majority of women have a clear preference for one AI compared to another based on side effects and quality of life. This finding of an individual preference for a specific AI is consistent with a previously published crossover study of anastrozole This is an invited commentary to article doi: 10.1007/s10549-010-1091-9.