RNAs, like proteins, readily form specific structures adapted for liga
nd binding and catalysis. Since they are composed of completely differ
ent chemical building blocks, however, RNAs and proteins necessarily u
se distinct strategies to assemble complex architectures. While burial
of hydrophobic residues drives protein folding, the hydrophobic effec
t in RNA contributes primarily to the formation of secondary structure
. To form tertiary structure, RNA must overcome electrostatic repulsio
ns from the phosphate backbone. How do negatively charged double helic
es pack together to produce catalytic centers and ligand binding surfa
ces? Here, we review our understanding of the principles that underlie
RNA folding based on the structural information currently available.