cutaneous Squamous cell carcinoma (cScc) is the most common and fastest-increasing cancer with metastatic potential. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression. To identify mRNAs, lncRNAs and circRNAs, which can be involved in cSCC, RNA-seq was performed on nine cSCCs and seven healthy skin samples. Representative transcripts were validated by NanoString nCounter assays using an extended cohort, which also included samples from pre-cancerous skin lesions (actinic keratosis). 5,352 protein-coding genes, 908 lncRNAs and 55 circular RNAs were identified to be differentially expressed in cSCC. Targets of 519 transcription factors were enriched among differentially expressed genes, 105 of which displayed altered level in cSCCs, including fundamental regulators of skin development (MYC, RELA, ETS1, TP63). Pathways related to cell cycle, apoptosis, inflammation and epidermal differentiation were enriched. In addition to known oncogenic lncRNAs (PVT1, LUCAT1, CASC9), a set of skin-specific lncRNAs were were identified to be dysregulated. A global downregulation of circRNAs was observed in cSCC, and novel skin-enriched circRNAs, circ_IFFO2 and circ_POF1B, were identified and validated. In conclusion, a reference set of coding and non-coding transcripts were identified in cSCC, which may become potential therapeutic targets or biomarkers. Cutaneous squamous cell carcinoma (cSCC) is one of the most common human malignancies worldwide, with an yearly 700,000 diagnosed cases in the US alone 1. This keratinocyte-derived cancer develops mostly on sun-exposed skin, proceeds as a progressively invasive malignancy, starting from precancerous lesions, actinic keratosis (AK), which can progress into invasive cSCC 2. The incidence of cSCC is increasing at an alarming rate worldwide majorly due to lifestyle changes, an ageing population and an increase in organ transplantations, which is a major risk factor for aggressive and multiple cSCCs 3. Although early stage cSCC is curable by surgical excision, metastatic cSCC has a poor long-term survival rate of 10-20% due to inefficacy of systemic chemotherapy 4. Thus, there is an urgent need to identify new druggable targets and pathways in cSCC. The most important risk factor for cSCC is a cumulative lifetime exposure to UV-B radiation. Consequently, cSCC has an extremely high mutational burden with approximately 50 mutations per mega-base coding sequence and driver mutations in key tumor suppressor genes (TP53 and NOTCH1/2) and oncogenes (HRAS and KRAS) 5. These early mutational events prime for oncogenic transformation through altered cell cycle, decreased apoptosis,