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In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Combining mouse genetics and in vivo ribosome profiling, we observe limb-patterning phenotypes in ribosomal protein (RP) haploinsufficient embryos, and we uncover selective translational changes of transcripts that controlling limb development. Surprisingly, both loss of p53, which is activated by RP haploinsufficiency, and augmented protein synthesis rescue these phenotypes. These findings are explained by the finding that p53 functions as a master regulator of protein synthesis, at least in part, through transcriptional activation of 4E-BP1. 4E-BP1, a key translational regulator, in turn, facilitates selective changes in the translatome downstream of p53, and this thereby explains how RP haploinsufficiency may elicit specificity to gene expression. These results provide an integrative model to help understand how in vivo tissue-specific phenotypes emerge in ribosomopathies. [Display omitted] • Ribosomal protein haploinsufficiency in mouse limb causes patterning defects • A p53-dependent translational regulatory program contributes to this phenotype • p53 regulates translation through induction of 4E-BP1, a translation repressor • Ribosome profiling reveals p53-dependent and -independent translational changes Tiu, Kerr, et al. show that ribosomal protein (RP) haploinsufficiency in the developing mammalian limb leads to patterning defects driven in part by p53-mediated translational regulation through induction of 4E-BP1, a translational repressor. This finding integrates p53 and translational dysregulation into a cohesive in vivo model of RP haploinsufficiency. [ABSTRACT FROM AUTHOR]