AbstractHere we analyze limb development after the conditional inactivation of Fgf8 from the epiblast, using the previously described MORE (Mox2Cre) line. This line drives variable mosaic recombination of a floxed Fgf8 allele, resulting in a small proportion of AER cells that maintain Fgf8 expression. The phenotype of Mox2Cre;Fgf8 limbs is most similar to that of Msx2Cre;Fgf8 forelimbs, indicating that a small but durable expression of FGF8 is equivalent to an early normal, but transitory, expression. This functional equivalence likely relies on the subsequent Fgf4 upregulation that buffers the differences in the pattern of Fgf8 expression between the two conditional mutants. The molecular analysis of Mox2Cre;Fgf8 limbs shows that, despite Fgf4 upregulation, they develop under reduced FGF signaling. These limbs also exhibit an abnormal area of cell death at the anterior forelimb autopod, overlapping with an ectopic domain of Bmp7 expression, which can explain the abnormal morphogenesis of the anterior autopod. Developmental Dynamics 237:649–658, 2008. © 2008 Wiley‐Liss, Inc.