The stability of messenger RNA (mRNA) is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for Saccharomyces cerevisiae explaining 60% of the half-life variation between genes based on mRNA sequence features alone, and predicts half-life at a median relative error of 30%. The model integrates known cis-regulatory elements, identifies novel ones, and quantifies their contributions at single-nucleotide resolution. We show quantitatively that codon usage is the major determinant of mRNA stability. Nonetheless, single-nucleotide variations have the largest effect when occurring on 3'UTR motifs or upstream AUGs. Application of the approach to Schizosaccharomyces pombe supports the generality of these findings. Analyzing the effect of these sequence elements on mRNA half-life data of 34 knockout strains showed that the effect of codon usage not only requires functional decapping and deadenylation, but also the 5'-to-3' exonuclease Xrn1, the non-sense mediated decay proteins Upf2 and Upf3, and does not require no-go decay. Altogether, this study quantitatively delineates the contributions of mRNA sequence features on stability in yeast, reveals their functional dependencies on degradation pathways, and allows accurate prediction of half-life from mRNA sequence.