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The tissue selectivity of a new generation of selective androgen receptor modulators (SARMs) was characterized in castrated and intact male rats. Studies focused on two SARMs, S-1 and S-4. In castrated animals, SARMs showed strong agonist activity in the anabolic tissues by maintaining and/or restoring castration induced loss in levator ani muscle mass, soleus muscle strength, and total body bone mineral density; but weak agonist activity in maintaining and stimulating prostate growth. In the presence of endogenous androgens, S-1 and S-4 behaved as antagonists in the prostate. Furthermore, SARM also showed agonist activity in the pituitary, which could help maintain the feedback regulation of plasma LH and FSH levels. SARMs were orally available, and showed strong anabolic activity after oral administration in the castrated animals. The tissue-selective agonist activity of SARMs in the anabolic tissues and the pituitary suggests that this novel class of nonsteroidal AR ligands might serve as better alternatives for male hormone replacement therapy and treatment of benign prostate hyperplasia (BPH). In vitro experiments using transiently expressed human 5α-reductase showed that SARMs were not substrates for 5α-reductase. The tissue selectivity of SARM was more related to the fact that testosterone activity in the prostate is amplified by conversion to dihydrotestosterone (DHT), a more potent androgen receptor agonist, while SARM activity was not amplified. Metabolism studies identified the deacetylated metabolite of S-4. Although species differences were observed in S-4 metabolism due to the species difference in N-acetyltransferase expression, the metabolite was not active and could not contribute to the pharmacologic activity of S-4. Gene expression profiling using a prostate cancer cell line, LNCaP, revealed the ligand-specific regulation of gene expression by S-4 as compared to DHT, suggesting that the tissue selectivity might not be simply due to the differences in the potency of these two ligands. In conclusion, S-1 and S-4 demonstrated tissue-selective pharmacologic effects with or without the presence of endogenous androgens. In vitro and in vivo studies showed that the tissue selectivity of SARMs could be related to the tissue specific expression of 5α-reductase and ligand-specific regulation of gene expression in the prostate.