Antihistamine drugs are one of the therapeutic classes most used at world level, at all ages and in multiple situations. Although in general they have a good safety profile, only the more recent drugs (second generation antihistamines) have been studied specifically with regard to the more important safety aspects. Given the variety of antihistamine drugs, they cannot all be considered equivalent in application to various special clinical situations, so that the documented clinical experience must be assessed in each case or, in the absence of such, the particular pharmacological characteristics of each molecule for the purpose of recommendation in these special situations. In general, there are few clinical studies published for groups of patients with kidney or liver failure, with concomitant multiple pathologies (such as cardiac pathology), in extremes of age (paediatrics or geriatrics) and in natural stages such as pregnancy or lactation, but these are normal situations and it is more and more frequent (among the elderly) for antihistamine drugs to be recommended. This review sets out the more relevant details compiled on the use of antihistamines in these special situations.