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Cutaneous T-cell lymphoma (CTCL) is a group of malignancies derived from skin-homing T cells. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common CTCL variants. In recent years, the genetic landscape of SS/MF has been characterized using genome-wide next-generation sequencing approaches. These studies have revealed that genes subjected to oncogenic mutations take part in cell cycle regulation, chromatin modification, Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT) signaling, T-cell receptor (TCR)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and microtubule associated protein kinase (MAPK) signaling, which suggests that deregulation of these cellular processes underlies lymphomagenesis. These studies provide the groundwork for functional and clinical studies that will lead to better risk assessment and more effective therapeutic approach in CTCL patients.