Toxicogenomics applications are increasingly applied to the evaluation of preclinical drug safety, and to explain toxicities associated with compounds at the mechanism level. In this review, we aim to describe the application of toxicogenomics tools for studying the genotoxic effect of active compounds on the gene-expression profile of A375 human malignant melanoma cells, through the other molecular functions of target genes, regulatory pathways and mechanisms of malignant melanomas. It also includes the current systems biology approaches, which are very useful for analyzing the biological system and understanding the entire mechanisms of malignant melanomas. We believe that this review would be very potent and useful for studying the toxicogenomics of A375 melanoma cells, and for further diagnostic and therapeutic applications.