In 1978, Michael Soule and Bruce Wilcox organised a meeting in San Diego which laid the foundations for many of the important issues in conservation biology. While genetic deterioration is perhaps not the the most important factor in species extinction, two principles have emerged, namely the need to maintain genetic variation for future genetic change, and to avoid loss in fitness arising from inbreeding depression. These two issues have been embodied in the so-called 50/500 rule. Despite much empirical and experimental observation, the genetics underlying the maintenance of genetic variation, and the nature of inbreeding depression, remain obscure. While both of these principles have been generally accepted, the conclusions that form the basis of this rule have been challenged. This talk revisits these issues in the light of our increased knowledge over the almost 40 years since the 1978 meeting.