Multiplicity in clinical trials may appear under several different guises: multiple endpoints, multiple treatment arm comparisons, and multiple looks at the data during interim monitoring, to name a few. It is well recognized by statisticians and nonstatisticians alike that multiplicity inflates the type I error rate of the experiment, and this has prompted the development of many multiple comparison adjustment procedures. What has remained one of the thornier and more controversial points of contention among trialists today is the philosophy surrounding the need for multiplicity adjustment in clinical trials. This paper provides guidelines on how to deal with this complex issue in a practical manner. Through a series of scenarios and examples, we illustrate the fundamental issues surrounding the concept of multiplicity and point to some key questions one should ask when deliberating on the necessity and extent of adjustment for multiple comparisons. Control Clin Trials 2000;21:527-539