The fragile X mental retardation protein (FMRP) contains three RNA binding domains, two of which the KH2 domain and the C-terminal arginine-glycine-rich (RG-rich) region participate in RNA binding. Because fragile X syndrome is the leading cause of inherited mental retardation, there has been an intensive search for the messenger RNA (mRNA) targets that interact with FMRP in vivo. Initial work led to the conclusion that FMRP binds to a nucleic acid tertiary structure element called a G-quartet. Recent studies have shown that FMRP also binds mRNAs containing U-pentameric sequences. Interestingly, both motifs are mimicked by homoribopolymers (poly (rG) and poly (rU)) that were first used to determine that FMRP functioned as an RNA binding protein. The consequences of these discoveries and future areas of investigation are discussed. (C) 2003 Elsevier Inc. All rights reserved.