IGF-I and members of the FGF family have been implicated in the reciprocal interactions between the apical ectodermal ridge (AER) and underlying subridge mesoderm that are required for outgrowth of the developing limb bud. Several FGFs are expressed by the AER and appear to mediate its outgrowth and patterning effects on the subridge mesoderm. IGF-I is expressed by the subridge mesoderm that is growing out in response to the AER, and exogenous IGF-I can promote the outgrowth of the subridge mesoderm in the absence of the AER. Maintenance of IGF-I expression by the subridge mesoderm is dependent on the AER. Here we report that exogenous FGF-2 and FGF-4 can substitute for the AER in maintaining IGF-I expression by the posterior subridge mesoderm of the chick limb bud. Furthermore, we have found that neutralizing antibodies against IGF-I inhibit the ability of FGFs to promote the outgrowth and proliferation of the posterior subridge mesoderm cultured in the absence of the AER. These results indicate that FGFs secreted by the AER maintain IGF-I expression by the subridge mesoderm, and that the ability of FGFs to promote the outgrowth and proliferation of limb mesoderm is dependent on IGF-I activity. Interestingly, however, the ability of FGFs to maintain the expression of the homeobox containing gene Msx-1 by the subridge mesoderm is not dependent on IGF-I activity.