This paper discusses genotoxicity testing and data interpretation as applied in The Netherlands in the context of the regulation of chemicals. Guidelines were first formulated in 1981 and their use evolved in practice, on the basis of increasing experience at the national and international levels. The distinction between in vitro assays to detect intrinsic genotoxic properties and in vivo assays as a subsequent phase to show the realization of this potential in an intact organism has always been a cornerstone of the Dutch approach. Several critical aspects of the use of short-term genotoxicity tests in sequential schemes are discussed, such as their predictivity for carcinogenicity, the limited database concerning the performance of short-term in vivo assays, the relevance of devising separate strategies to test for possible carcinogenicity and germ cell mutagenicity, and the use of short-term tests to discriminate between genotoxic and non-genotoxic carcinogens. Examples are given of how short-term tests contributed to the toxicological evaluation of chemicals in The Netherlands.