Caffeine, a biologically active drug with many known molecular targets, is recognized as a contaminant of marine systems. Although the concentrations of caffeine reported from aquatic systems are low (ng/l-μg/l), harmful ecological effects not detected by traditional toxicity tests could occur as a result of caffeine contamination. We used Hsp70, a molecular biomarker of cellular stress, to investigate the sub-lethal cellular toxicity of environmentally relevant concentrations of caffeine on the mussel Mytilus californianus, a dominant species in the rocky intertidal zone along the Oregon Coast. Hsp70 concentrations in the gill and mantle tissue of mussels exposed to 0.05, 0.2, and 0.5 μg/l of caffeine for 10, 20, and 30 days were compared to basal levels in control mussels. Hsp70 in the gill tissue of M. californianus had an initial attenuation of the stress protein followed by a significant up-regulation relative to controls in all but the 0.5 μg/l treatment. Hsp70 in the mantle tissue of mussels exposed to caffeine did not differ from control mussels. This study provides laboratory evidence that environmentally relevant concentrations of caffeine can exert an effect on M. californianus gill tissue at the molecular-level.