The complete cohort of molecules involved in interdigital cell death (ICD) and their interactions are yet to be defined. Bmp proteins, retinoic acid (RA) and Fgf8 have been previously identified as relevant factors in the control of ICD. Here we determined that downregulation of Fgf8 expression in the ectoderm overlying the interdigital areas is the event that triggers ICD, whereas RA is the persistent cell death-inducing molecule that acts on the distal mesenchyme by a mechanism involving the induction of Bax expression. Inhibition of the mitogen-activated protein kinase (Mapk) pathway prevents the survival effect of Fgf8 on interdigital cells and the accompanying Erk1/2 phosphorylation and induction of Mkp3 expression. Fgf8 regulates the levels of RA by both decreasing the expression of Raldh2 and increasing the expression of Cyp26b1, whereas RA reduces Fgfr1 expression and Erk1/2 phosphorylation. In the mouse limb, inhibition of Bmp signaling in the mesenchyme does not affect ICD. However, noggin in the distal ectoderm induces Fgf8 expression and reduces interdigit regression. In the chick limb, exogenous noggin reduces ICD, but, when applied to the distal mesenchyme, this reduction is associated with an increase in Fgf8 expression. In agreement with the critical decline in Fgf8 expression for the activation of ICD, distal interdigital cells acquire a proximal position as interdigit regression occurs. We identified proliferating distal mesenchymal cells as those that give rise to the interdigital cells fated to die. Thus, ICD is determined by the antagonistic regulation of cell death by Fgf8 and RA and occurs through a progressive, rather than massive, cell death mechanism.