It is evident that no chemotherapy regimen can be considered standard for patients with ACUP. If after careful evaluation, a patient does not belong to a subset of patients with a higher chance of response, then the low likelihood of response to systemic therapy and the potential for treatment-associated toxicities must be reviewed with the patient. Should a trial of chemotherapy be chosen, this must be attempted with close monitoring for toxicity and should be discontinued unless a clear response is observed after a set time period, eg, two cycles of therapy. An effort should be made to ascertain whether there is a clinical protocol available at a regional center for which the patient would be eligible. For patients treated in a noninvestigational setting, we suggest a regimen such as FAM because of its relative tolerability and ease of administration. The most promising avenue for further study, and hopefully for future clinical practice, is the more precise identification of factors associated with a clearly defined response rate (either higher or lower) than patients with ACUP in general. The utilization of newer pathological or in vitro techniques for the study of these tumors should be encouraged as part of clinical trials because they may increase the number of patients who belong to specific subsets of ACUP associated with well-characterized responses to appropriate chemotherapy.