There are several mRNA surveillance pathways in eukaryotes (NGD, NSD and NMD) that moderate the effects of natural errors in the cell and more broadly regulate gene expression. We have previously defined biochemical parameters of the factors Dom34, Hbs1 and Rli1 in our in vitro reconstituted yeast translation system. We have correlated these biochemical observations with ribosome profiling experiments in yeast to broadly define the in vivo targets of these same mRNA surveillance pathways. In the process of studying these pathways, we have learned that different ribosome footprint (RPFs) sizes represent distinct states of the ribosome in a cell, and that these signatures can inform us on the molecular stresses that the ribosomes encounter. We are currently defining how the cell responds to these molecular triggers. Other studies in mammalian platelets and reticulocytes revealed the accumulation of ribosomes in the 3’ UTR of mRNAs and we connected this phenomenon with diminished levels of ribosome rescue (DOM34/HBS1L) and recycling (ABCE1) factors in these systems. We are currently drawing together related observations in the yeast and mammalian systems to better define the factors and mechanisms that maintain cellular ribosome homeostasis and to explore how it impacts development and stress-responses.