In prescription surveys, use of combination antipsychotics is common and is increasing, despite little supporting evidence. This article highlights potential problems with using combination antipsychotics, discusses paths to their maintenance use, and reviews the efficacy evidence. Paths to maintenance antipsychotic combinations include (1) failure or patient refusal of all reasonable monotherapies, (2) indefinite continuation of combinations initially intended to be brief, (3) trials of combinations in preference to reasonable monotherapy trials, and (4) addition of a second antipsychotic to counteract a problem (safety, tolerability, or adherence) arising during successful monotherapy. Virtually all of the evidence on combination antipsychotics is on augmentation of clozapine, with only one randomized controlled trial. Research on combination antipsychotics is sorely needed. Designing clinical trials is made difficult by the very large numbers of possible combinations and doses. It may be feasible to analyze existing data bases to identify combinations that appear particularly promising to investigate.