The stability of messenger RNA (mRNA) is one of the major determinants of gene expression. Although a wealth of sequence elements and mechanisms regulating mRNA stability has been described, their quantitative contributions in determining mRNA half-life is unknown. Here, we built quantitative models for two eukaryotic genomes Saccharomyces cerevisiae and Schizosaccharomyces pombe that, for the first time, explain most of the half-life variation between genes based on mRNA sequence alone. The models integrate known functional cis-regulatory elements, identify novel ones, and quantify their contributions at single-nucleotide resolution. We show quantitatively that codon usage is the major determinant of mRNA stability, and that this effect depends on canonical mRNA degradation pathways. Altogether, our results integrate and quantitatively delineate mRNA stability cis-regulatory elements and provide a methodology that can serve as a scaffold to study the function of cis-regulatory elements and to discover novel ones.