The World Health Organisation’s Prequalification of Medicines Programme (WHO PQP) evaluates generic medicines for the treatment of HIV/AIDS, malaria, tuberculosis, influenza, and neglected tropical diseases, as well as zinc for the treatment of acute diarrhoea, and generic products related to reproductive health. For in vivo (i.e. bioequivalence studies) or in vitro studies (i.e. Biopharmaceutics Classification System-based biowaivers) used to establish the safety and efficacy of a generic product, selection of an appropriate comparator product is of great importance. Generic products prequalified by the WHO PQP are used in treatment programmes on a worldwide basis and therefore, the comparator products acting as a reference for their safety and efficacy should be of globally accepted quality, safety, and efficacy. Thus, to provide guidance to potential applicants and to discourage submission of bioequivalence studies with a comparator product that is not acceptable for the WHO PQP, comparators have been identified which should be employed in bioequivalence or biowaiver studies undertaken for submission to WHO PQP. The comparator of choice is normally the innovator product for which the quality, safety and efficacy have been established. In addition, to ensure that the comparator product has been adequately controlled from production to use, WHO PQP stipulates that comparator products should be procured from markets with a stringent regulatory authority, i.e. from countries participating in ICH or an ICH-associated country. However there can be many challenges associated with identifying appropriate comparators for WHO PQP. These challenges, ranging from the absence of a clear innovator product to the unavailability of a well-established innovator product to availability limited to non-ICH-associated markets, are discussed and the selections of specific comparator products supported. Furthermore, clear guidance on procuring the WHO PQP comparator are given, establishing further confidence that an appropriate comparator has been selected with proven quality, safety and efficacy.