Background: Carcinogenesis affects not only humans but almost all metazoan species. Understanding the rules driving the occurrence of cancers in the wild is currently expected to provide crucial insights into identifying how some species may have evolved efficient cancer resistance mechanisms. Recently the absence of correlation across species between cancer prevalence and body size (coined as Peto's paradox) has attracted a lot of attention. Indeed, the disparity between this null hypothesis, where every cell is assumed to have an identical probability to undergo malignant transformation, and empirical observations is particularly important to understand, due to the fact that it could facilitate the identification of animal species that are more resistant to carcinogenesis than expected. Moreover it would open up ways to identify the selective pressures that may be involved in cancer resistance. However, Peto's paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences. Discussions: Here we review and challenge the different hypotheses on which this paradox relies on with the aim of identifying how this null hypothesis could be better estimated in order to provide a standard protocol to study the deviation between theoretical/theoretically predicted and observed cancer incidence. We show that due to the disproportion and restricted nature of available data on animal cancers, applying Peto's hypotheses at species level could result in erroneous conclusions, and actually assume the existence of a paradox. Instead of using species level comparisons, we propose an organ level approach to be a more accurate test of Peto's assumptions. Summary: The accuracy of Peto's paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto's paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms.