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We investigated the underlying mechanism of the inhibition of \u03b21\/2\u2010ARs signaling for the treatment of CRC and elucidated the significance of \u03b22\u2010AR expression in CRC in vitro and in clinical samples. The impacts of \u03b21\/2\u2010AR antagonists in CRC in vitro and CRC\u2010xenograft in vivo were examined. We found that repression of \u03b22\u2010AR but not \u03b21\u2010AR signaling selectively suppressed cell viability, induced G1\u2010phase cell cycle arrest, caused both intrinsic and extrinsic pathways\u2010mediated apoptosis of specific CRC cells and inhibited CRC\u2010xenograft growth in vivo. Moreover, the expression of \u03b22\u2010AR was not consistent with the progression of CRC in vitro or in clinical samples. Our data evidence that the expression profiles, signaling, and blockage of \u03b22\u2010AR have a unique pattern in CRC comparing to other cancers. \u03b22\u2010AR antagonism selectively suppresses the growth of CRC accompanying active \u03b22\u2010AR signaling, which potentially carries wild\u2010type <jats:italic>KRAS<\/jats:italic>, in vitro and in vivo via the inhibition of \u03b22\u2010AR transactivated EFGR\u2010Akt\/ERK1\/2 signaling pathway. Thus, \u03b22\u2010AR blockage might be a potential therapeutic strategy for combating the progressions of \u03b22\u2010AR\u2010dependent CRC. J. Cell. 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