Capecitabine is widely used in the management of metastatic breast cancer; however, drug delivery is limited by gastrointestinal and other toxicity. We employed mathematical modeling to rationally design an optimized dose and schedule for capecitabine of 2,000 mg twice daily, flat dosing, 7 days on, 7 days off. Preclinical data suggested increased efficacy and tolerability with this novel dosing, and three early-phase clinical trials have suggested a favorable toxicity profile. To further define the tolerability of this regimen, we conducted a systematic review of the gastrointestinal adverse events of patients on these studies. This review demonstrated a favorable gastrointestinal toxicity profile with capecitabine in this novel schedule when given as single agent or in combination therapy with either bevacizumab or lapatinib. No patients discontinued therapy for gastrointestinal toxicity, and there were no grade 4 or 5 gastrointestinal toxicities reported. Grade 3 or greater diarrhea occurred in two (2%); grade 2 or greater mucositis, constipation, and vomiting were reported in three (4%) patients. We conclude that capecitabine administered on a 7 days on, 7 days off schedule has limited gastrointestinal toxicity. Our methodology was based on an analysis of individual patient toxicity data from one phase I single-agent capecitabine and two phase II capecitabine combination studies (with bevacizumab and lapatinib, respectively), focusing specifically on gastrointestinal toxicity.