The classical paradigm of Phase III clinical research is to demonstrate efficacy of a drug in an unselected patient population representative for later clinical practice. The flip side of the coin is that homogeneity of the treatment effect in subpopulations of the patient population cannot be assumed to be trivially given. Close inspection of relevant subgroups is important, as soon as overall efficacy has been demonstrated. This may lead to restrictions regarding the patient population to be treated. Similarly, although subgroup findings may be misleading, it should be possible in rare instances to base valid conclusions on subgroups of trials where this has not been precisely prespecified. Subgroups in multiregional clinical trials are different and deserve special consideration.