The main sociological, philosophical and historical approaches only ascribe a relative importance to the role of chance, error, or accident in scientific progress. The literature on this topic tends to be anecdotal, sometimes hagiographic and rarely systematic. The main goal of this paper is to introduce a new approach to the study of serendipity in scientific discovery. This new approach is based in the study of highly cited papers obtained from theCitation Classics feature ofCurrent Contents. This paper re-examines 205Citation Classics commentaries from the 400 most-cited papers in the recent history of science. Authors of 17Citation Classics commentaries (8.3%) mention some kind of serendipity in performing the research reported in the highly cited paper. Commentaries are classified and discussed in detail. In addition, I have examinated the original papers identified above. In 5 from the original highly cited papers authors explained or gave enough hints on the way the serendipitous discovery was done.