Cre‐mediated excision of targeted loxP sites is widely used to delete or to activate gene expression in temporal or tissue‐specific fashions. We examine three previously described cre alleles and find that Cre activity alone causes dramatic developmental defects, such as loss of hematopoietic activity and dramatically upregulated apoptosis in many embryonic tissues in two of these lines. These results demonstrate that cre expression generates spurious phenotypes that can confound genetics analyses. We also find that most recently published studies fail to include cre‐positive controls, and thus may have attributed roles to a targeted gene, which were in reality partly or wholly due to Cre toxicity. This information will be critical in both evaluating previously published work using cre alleles and in designing future experiments. genesis 45:768–775, 2007. © 2007 Wiley‐Liss, Inc.