The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis been speculated for over sixty years. Recent advances in mass spectrometry and high throughput analysis have begun to identify and characterize distinct ribosome stoichiometry in yeast or mammalian systems. In addition to RP stoichiometry, ribosomes play host to a vast array of protein modifications, effectively expanding the number of human RPs from 80 to many thousands of distinct proteoforms. Is it possible these proteoforms combine to function as a 'ribosome code' to tune protein synthesis? We outline the specific benefits that translational regulation by specialized ribosomes can offer and discuss the means and methodologies available to correlate and characterize RP stoichiometry with function. We highlight previous research with a focus on formulating hypotheses that can guide future experiments and crack the 'ribosome code'.Ribosomes, the cellular machinery of protein synthesis, are present at up to ten million copies per cell in mammals. Despite their abundance and the wide array of known modifications to both ribosomal proteins (RPs) and rRNA, study of the direct role of the ribosome in tuning cellular translation has until recently taken a back seat to posttranscriptional regulation at the level of translation initiation. The hypothesis that ribosomes actively regulate protein synthesis as part of normal development and physiology dates back to the 1950s [1]. In the ensuing decades, numerous albeit inconclusive, observations have supported this hypothesis, and a subset of those are shown in Figure 1, color-coded by the type of evidence.For many years, the dominant 'abundance' model of translational regulation by the ribosome suggested a limited role for ribosomes in translation regulation [2]. In this model, if ribosomes have different initiation affinity for different transcripts, a global decrease in the availability of free ribosomes selectively decreases the initiation rates of different transcripts to varying degrees [2]. This mechanism, recently reviewed by Mills and Green [4], relies on the non-linear dependence of translation initiation on free ribosomes and applies quite generally. Indeed, recent research from the Sankaran lab suggested this mechanisms could explain the failure of erythroid lineage commitment seen with Diamond-Blackfan anaemia [5] 2 by the abundance model is limited in magnitude by the changes of total ribosomal content and in flexibility since it provides unidirectional regulation for all proteins.The concept of ribosome specialization In the 'specialized' ribosome model, ribosomes do not possess constant structure or composition (Figure 2A, B), and instead exhibit altered stoichiometry of what were previously thought to represent 'core' ribosomal proteins (Figure 1) [7,8]. In this model, different ribosomal compositions are functional and have specific roles in translation. Specialized ribosomes could co-exist within cells, or between ...