A unifying concept that combines the basic features governing self-organization of proteins into complex three-dimensional structures in vitro and in vivo is still lacking. Recent experimental results and theoretical in silico modeling studies provide evidence showing that mRNA might contain an additional layer of information, beyond the amino acid sequence, that fine-tunes in vivo protein folding, which is largely believed to start as a co-translational process. These findings indicate that translation kinetics might direct the co-translational folding pathway and that translational pausing at rare codons might provide a time delay to enable independent and sequential folding of the defined portions of the nascent polypeptide emerging from the ribosome.