A long non-coding RNA, TINCR, plays a critical role in controlling human epidermal differentiation through post-transcriptional mechanisms. TINCR is required for the high abundance of key differentiation genes, many of which are involved in skin diseases. TINCR-deficient epidermis lacks terminal differentiation ultrastructures, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs, with a 25-nucleotide 'TINCR box' motif being strongly enriched in interacting mRNAs and required for TINCR binding. TINCR directly binds to the staufen1 (STAU1) protein, and STAU1 deficiency recapitulates the impaired differentiation seen with TINCR depletion. TINCR and STAU1 together mediate the stabilization of differentiation mRNAs, such as KRT80. These findings identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression. TINCR is a differentiation-induced, predominantly cytoplasmic lncRNA. TINCR function was assessed by RNA interference in organotypic human epidermal tissue, a setting that recapitulates the structure and gene expression of human epidermis. TINCR-deficient epidermis showed reduced expression of key differentiation genes at both the protein and mRNA levels. Transcript profiling of TINCR-depleted epidermis demonstrated that TINCR loss disrupted the expression of 394 genes. TINCR-regulated genes were enriched for differentiation-associated epidermal barrier formation-related Gene Ontology (GO) terms. Barrier formation requires genes encoding the protein structure of the terminally differentiated stratum corneum, such as loricrin and filaggrin, as well as those synthesizing specific water-impermeable lipids. GO terms related to the latter were enriched in genes altered by TINCR loss. Caspase 14, implicated in proteolysis needed for epidermal barrier function, was diminished by 83.7% with TINCR loss. Protein and lipid barrier ultrastructures involved in barrier formation were abnormal in the outer layers of TINCR-deficient epidermis, including protein-rich keratohyalin granules and the lipid-rich lamellar bodies. Deficiencies in these structures are characteristic of human genodermatoses with abnormal skin barrier function. TINCR is thus required for the induction of genes that form the cellular structures that mediate differentiation-associated epidermal barrier formation. TINCR interacts with differentiation mRNAs through the TINCR box motif. Loss of the TINCR-associated cytoplasmic protein STAU1 resembles TINCR loss and demonstrates a new UPF1/2-independent role for STAU1A long non-coding RNA, TINCR, plays a critical role in controlling human epidermal differentiation through post-transcriptional mechanisms. TINCR is required for the high abundance of key differentiation genes, many of which are involved in skin diseases. TINCR-deficient epidermis lacks terminal differentiation ultrastructures, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs, with a 25-nucleotide 'TINCR box' motif being strongly enriched in interacting mRNAs and required for TINCR binding. TINCR directly binds to the staufen1 (STAU1) protein, and STAU1 deficiency recapitulates the impaired differentiation seen with TINCR depletion. TINCR and STAU1 together mediate the stabilization of differentiation mRNAs, such as KRT80. These findings identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression. TINCR is a differentiation-induced, predominantly cytoplasmic lncRNA. TINCR function was assessed by RNA interference in organotypic human epidermal tissue, a setting that recapitulates the structure and gene expression of human epidermis. TINCR-deficient epidermis showed reduced expression of key differentiation genes at both the protein and mRNA levels. Transcript profiling of TINCR-depleted epidermis demonstrated that TINCR loss disrupted the expression of 394 genes. TINCR-regulated genes were enriched for differentiation-associated epidermal barrier formation-related Gene Ontology (GO) terms. Barrier formation requires genes encoding the protein structure of the terminally differentiated stratum corneum, such as loricrin and filaggrin, as well as those synthesizing specific water-impermeable lipids. GO terms related to the latter were enriched in genes altered by TINCR loss. Caspase 14, implicated in proteolysis needed for epidermal barrier function, was diminished by 83.7% with TINCR loss. Protein and lipid barrier ultrastructures involved in barrier formation were abnormal in the outer layers of TINCR-deficient epidermis, including protein-rich keratohyalin granules and the lipid-rich lamellar bodies. Deficiencies in these structures are characteristic of human genodermatoses with abnormal skin barrier function. TINCR is thus required for the induction of genes that form the cellular structures that mediate differentiation-associated epidermal barrier formation. TINCR interacts with differentiation mRNAs through the TINCR box motif. Loss of the TINCR-associated cytoplasmic protein STAU1 resembles TINCR loss and demonstrates a new UPF1/2-independent role for STAU1