Insulin growth factors (IGFs) are important determinants of fetal growth and development. Pregnancy-associated plasma protein A (PAPPA) modulates the bioavailability and mitogenic activity of IGFs in vitro by regulating the cleavage of the IGF-binding protein, IGFBP4. Conover et al.(p. 1187) now determine the role of PAPPA in vivo and find that it has striking effects on growth during early embryogenesis. They find that PAPPA-null mice are proportional dwarfs, only 60% the size of wild-type mice, with remarkable similarity to IGF2-null mice. Furthermore, PAPPA mRNA colocalises with IGF2 and IGFBP4 transcripts during the development of wild-type embryos. In PAPPA-null mice, IGF2 and IGFBP4 mRNA localisation is unchanged but IGFBP4 is not cleaved and IGF-stimulated mitogenesis is inhibited. Thus, Conover and co-workers provide the first evidence that PAPPA functions as an essential growth regulator by regulating IGF bioavailability during early fetal development.