Transcriptional profiling can elucidate adaptive/toxicity pathways participating in achieving homeostasis or leading to pathogenesis in marine biota exposed to chemical substances. With the aim of analyzing transcriptional responses in the mussel Mytilus edulis exposed to the corrosive and putatively carcinogenic hydrocarbon styrene (3–5 ppm, 3 days), a forward subtracted (SSH) cDNA library was produced. Female mussels were selected and digestive gland mRNA was isolated. A library with 1440 clones was produced and a total of 287 clones were sequenced, 53% being identified through BlastN analysis against Mytibase and DeepSeaVent databases. Those genes included GO terms such as ‘response to drugs’, ‘immune defense’ and ‘cell proliferation’. Furthermore, sequences related to chitin and beta-1-3-glucan metabolism were also up-regulated by styrene. Many of the obtained sequences could not be annotated constituting new mussel sequences. In conclusion, this SSH study reveals novel sequences useful to generate molecular biomarkers of styrene exposure in mussels.