Ribosome profiling has proved to be a fantastic innovation which has revealed so much about mRNA translation that had previously gone unrecognized. The RNA community owes Jonathan Weissman and Nick Ingolia a deep sense of gratitude for conceiving the approach in the first place, and for their detailed optimization of the methodology. The origins of the approach can be traced back to the discovery of polysomes over 50 years ago, and the finding that treatment with endoribonucleases converted them to monomeric ribosomes that were each bound to a short protected mRNA fragment. This was first exploited by Joan Steitz and Marilyn Kozak to identify and sequence the translation initiation sites of prokaryotic bacteriophage RNA and eukaryotic reovirus RNAs, respectively; and extended by Sandra Wolin and Peter Walter to reveal ribosome pausing at the initiation and termination codons of preprolactin mRNA, as well as at the point at which SRP interacts with the nascent protein. Because of the limitations of sequencing methods available in that era, these experiments necessarily used cell-free translation systems programmed preferably with a single mRNA species (or a maximum of 4 reovirus mRNAs).