Understanding the metastatic potential of a skin cancer is essential to effective management. Gene expression profiling (GEP) is an innovative technology that has allowed for a better understanding of tumor biology in various skin cancers. Current methods focus on identifying and quantifying ribonucleic acid (RNA) transcripts in tissue samples. Using reverse transcriptase-polymerase chain reaction, specific RNA transcripts are reverted into deoxyribonucleic acid (DNA) for quantification. The addition of RNA-seq has further enhanced our knowledge of genomes not only by measuring known sequences, but also by identifying novel genes in various skin cancers. GEP requires only a small amount of RNA and has a high level of reproducibility. Using this technology, several GEPs for skin cancers have been developed to augment diagnosis and prognosis of skin cancer. This article reviews the process of gene expression profiling and the current GEPs that are available or under investigation for skin cancer. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7017.