This study investigates the role of a long non-coding RNA (lncRNA), terminal differentiation-induced ncRNA (TINCR), in human epidermal differentiation. TINCR is a 3.7-kilobase lncRNA that is highly induced during epidermal differentiation and is associated with key differentiation genes mutated in human skin diseases. The authors found that TINCR is essential for maintaining high levels of mRNA expression of these genes and for the formation of ultrastructural features of differentiated epidermis, such as keratohyalin granules and lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs through a 25-nucleotide 'TINCR box' motif. High-throughput screening identified direct binding of TINCR to the staufen1 (STAU1) protein, which is a known RNA-binding protein. Depletion of STAU1 recapitulated the impaired differentiation seen with TINCR depletion. However, loss of UPF1 and UPF2, which are required for STAU1-mediated RNA decay, did not affect differentiation. Instead, the TINCR-STAU1 complex appears to mediate the stabilization of differentiation mRNAs, such as *KRT80*. These findings identify TINCR as a key lncRNA required for somatic tissue differentiation, acting through lncRNA binding to differentiation mRNAs to ensure their expression.This study investigates the role of a long non-coding RNA (lncRNA), terminal differentiation-induced ncRNA (TINCR), in human epidermal differentiation. TINCR is a 3.7-kilobase lncRNA that is highly induced during epidermal differentiation and is associated with key differentiation genes mutated in human skin diseases. The authors found that TINCR is essential for maintaining high levels of mRNA expression of these genes and for the formation of ultrastructural features of differentiated epidermis, such as keratohyalin granules and lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs through a 25-nucleotide 'TINCR box' motif. High-throughput screening identified direct binding of TINCR to the staufen1 (STAU1) protein, which is a known RNA-binding protein. Depletion of STAU1 recapitulated the impaired differentiation seen with TINCR depletion. However, loss of UPF1 and UPF2, which are required for STAU1-mediated RNA decay, did not affect differentiation. Instead, the TINCR-STAU1 complex appears to mediate the stabilization of differentiation mRNAs, such as *KRT80*. These findings identify TINCR as a key lncRNA required for somatic tissue differentiation, acting through lncRNA binding to differentiation mRNAs to ensure their expression.