In order to test hypotheses prospectively with hard data and against placebo, the scientific method of clinical trials has been developed. The present paper focuses on specific problems associated with the use of a placebo control group. (a) The placebo highlights the ethical dilemma that a controlled clinical trial can place us in. (b) Also, in a trial an atmosphere is created of enhanced risks of placebo effects. (c) "Significantly different from placebo" does not necessarily mean clinically relevant. (d) A biased placebo period due to carry-over effect is a common problem of controlled trials with a cross-over or self-controlled design. (e) Likewise an asymmetric placebo group is also a common problem in parallel-group designs. (f) The response to a placebo is generally small in comparison with the response to active treatment and is therefore sometimes more susceptible to bias. It is emphasized that routinely accounting for such problems may further improve the powerful method of controlled clinical trials.