4-one) is an isoflavone which has been proposed as a potential drug for the use in substrate reduction therapy (SRT) in mucopolysaccharidoses and other lysosmal storage diseases (LSD). It was proposed that the effect of genistein to reduce the lysosomal storage is due to inhibition of phosphorylation of epidermal growth factor receptor, thus, impairing the signal transduction mechanism that normally leads to activation of expression of genes coding for enzymes necessary in biochemical reactions leading to production of glycosaminoglycans (GAG) and possibly other compounds. However, to learn about the exact mechanism(s) of action of genistein, we have performed transcriptomic analyses. Cultures of human dermal fibroblasts were treated with genistein and transcriptomic signatures were determined. Time points assessed for 0.03, 0.06 and 0.1 mM genistein included 1, 24 and 48 h. The microarray analysis was performedwith the use of HumanHT-12 Expression BeadChip. Significant differences in expression of between 259 and 631 genes, depending on genistein concentration and the time of treatment, were detected. Among the affected genes, 74 coded for proteins with known functions in lysosomal biogenesis and/or function. Of these proteins, nearly 50% are associated with human lysosomal diseases. Particularly, genistein regulated expression of some genes coding for enzymes required for synthesis or degradation of GAG and glycosphingolipids. Moreover, expression of many genes involved in secondary effects of LSD was found to be modulated by genistein. Therefore, it appears that the mechanism of genistein-mediated SRT is significantly more complicated than just reduction in GAG synthesis.