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Background: Prostate is a well-known androgen-dependent tissue., Methods: By sequencing 4,294,186 serial analysis of gene expression (SAGE) tags, we have investigated the transcriptomes of normal mouse prostate, liver, testis, lung, brain, femur, skin, adipose tissue, skeletal muscle, vagina, ovary, mammary gland, and uterus in order to identify the most abundant and tissue-specific transcripts in the prostate, as well as to target the androgen responsive transcripts specifically regulated in the prostate. Small interference RNA (siRNA) in LNCaP cells was applied to validate the roles of prostate-specific/enriched ARGs in the growth of human prostate cancer cells., Results: The most abundant transcripts were involved in prostatic secretion, energy metabolism and immunity. Previously well-known prostate-specific transcripts, including many transcripts involved in prostatic secretion, polyamine biosynthesis and transport, and immunity were specific/enriched in the prostate. Only 22 transcripts among 114 androgen-regulated genes (ARGs) in the mouse prostate were modulated by dihydrotestosterone (DHT) in two or more tissues. The siRNA results showed that inhibition of HSPA5 and MAT2A gene expression repressed growth of human cancer LNCaP cells., Conclusions: The current study globally assessed the transcriptome of the prostate and revealed the most abundant and tissue-specific transcripts which are responsible for the unique functions of this organ. These prostate-specific ARGs might be used as targets to develop safe and effective gene-based therapy for the prevention and treatment of prostate cancer.