Cellular protein levels depend upon their synthesis and degradation rates (i.e protein turnover). Characterizing protein turnover is thus essential for determining cell response to different stimuli but the main determinants of this process are poorly understood. We comprehensively addressed this by applying a systems biology approach integrating protein stability with physical, biological and genetic information in yeast. The analysis of >3000 protein abundances and half-lives by pulsed SILAC support a pro-degradative design (i.e. higher lysine density, accumulation of ubiquitylation sites in C-terminal and increase of proteolytic degradation signs) for unstable proteins. However, functional characteristics of proteins, such as localization, connectivity and activity, are also a major determinants of protein stability. We also provide evidence of a synchronization between protein and mRNA stabilities in exponentially growing yeast. Finally, we showed that stress induced changes in protein and transcript abundance are directly correlated to changes in protein turnover.This study establish the bottom line for future studies aimed at deciphering protein turnover regulation