Pseudo-albinism is a complex condition, caused by a multitude of factors and negatively affecting flatfish aquaculture. The majority of studies have targeted genes involved in pigmentation, the most notable change in these animals. In this study, a global transcriptome approach was taken to understand the underlying basis of Senegalese sole pseudo-albinism, using as targets two important innate immune barriers, the skin and intestine. RNA-seq transcriptome analysis identified 573 differentially expressed transcripts (DETs) between pseudo-albino and pigmented soles in the skin and/or the gut. DETs were mainly linked to pigment production, skin structure and regeneration, mucus production and smooth muscle contraction.