mRNA stability is a critical determinant of normal red blood cell development and function. The long half-life of globin mRNA is central to the continued synthesis of globin proteins throughout all stages of erythropoiesis, even as the cells undergo programmed transcriptional arrest during terminal differentiation. Studies of a naturally occurring alpha-thalassemic mutation that triggers marked destabilization of alpha-globin mRNA first led investigators to search for a stability determinant in the 3'-untranslated region (3'UTR). Analysis of this region identified three cytosine-rich (C-rich) segments that contributed to alpha-globin mRNA stability when studied in transfected erythroid cells. Subsequently, in vitro studies demonstrated assembly of a sequence-specific ribonucleic-protein (RNP) complex at this site. Mutations in the 3'UTR that blocked formation of this "alpha-complex" in vitro resulted in a parallel destabilization of alpha-globin mRNA in transfected cells. Members of the alpha-globin poly(C)-binding protein (alphaCP) subfamily of heteronuclear (hn) RNP K homology (KH) domain RNA-binding proteins have been identified as essential protein components of the alpha-complex. In vitro studies suggested that additional proteins may also contribute to alpha-complex structure and/or function. Surveys of additional highly stable mRNAs point to a general function for the alpha-complex in mRNA stabilization. In vitro and in vivo analyses indicated that the alpha-complex stabilizes alpha-globin mRNA by two mechanisms: control of 3'-terminal deadenylation and steric protection of an endoribonuclease-sensitive site. Confirmation of these pathways, determination of their relative importance, and generalization of these findings to additional systems await future studies.