This review focuses on the methodology and interpretation of drug trials in peptic ulcer disease. The problems of planning and conduct that are discussed include the ethics of using placebo, eligibility criteria, estimations of sample size, stopping rules, randomization, blinding, and efficacy criteria, that is, ulcer healing and pain relief in the short term and prevention of relapse and complications in the long term. Statistical topics covered include confidence intervals, evaluation of survival type data, post-stratification, and sub-group analysis. The difference between clinical and statistical significance is discussed, major problems being overemphasis on P-value, type II errors, and post hoc power determinations. Explanatory and pragmatic questions are based on compliance-to-protocol and intention-to-treat cohorts, respectively, and involve problems of compliance testing, evaluation of withdrawals, and the use of fixed-dose regimens. The rather slow process for clinical trials to gain acceptance is described, and it is proposed to rely on disease-related and behavioural barriers, lack of knowledge of the inherent limitations of methodology, and overemphasis on the subject of peptic ulcer healing, in addition to some concern at the relevance of assessing long-term drug intervention by repeated endoscopies rather than by studying symptoms and the incidence of complications. We foresee an increased impact of clinical trials on ulcer research and therapeutic decision making, provided physicians are able to develop the proper methodology to answer the relevant questions.