5'-3' RNA decay pathways are critical for quality control and regulation of gene expression. Structural and biochemical studies have provided insights into the key nucleases that carry out deadenylation, decapping, and exonucleolysis during 5'-3' decay, but detailed understanding of how these activities are coordinated is only beginning to emerge. Here we review recent mechanistic insights into the control of 5'-3' RNA decay, including coupling between translation and decay, coordination between the complexes and activities that process 5' and 3' RNA termini, conformational control of enzymatic activity, liquid phase separation, and RNA modifications.