Cardiac hypertrophy is increase in myocardial mass in response to stress or injury and has been identified as a potential target in the prevention of heart failure. Cardioprotective effects of resveratrol has been widely reported, however low bioavailability limits clinical use. Resveratrol, gnetol (lower bioavailability) and pterostilbene (higher bioavailability) belong to the group of stilbenoid polyphenols. Activation of AMP-activated protein kinase (AMPK), a key energy balance sensor, via phosphorylation at thr-172 is known to be protective and prevent the development of cardiac hypertrophy. Microphthalmia-associated transcription factor (MITF) is a transcription factor involved in melanogenesis. The novel role of MITF in cardiac hypertrophy has been recently identified in the literature. Here I queried first, the anti-hypertrophic effects of gnetol and pterostilbene and the involvement of AMPK and MITF in vitro. Secondly, I examined the cardioprotective effects and the role of bioavailabilities of resveratrol, gnetol and pterostilbene in vivo using spontaneously hypertensive heart failure (SHHF) rats. Effects of gnetol and pterostilbene on ET-1-induced hypertrophy were determined: cell size by immunostaining and computer-assisted planimetry, protein synthesis measured by Click-iT® protein synthesis assay kit and fetal gene (BNP) expression by real time PCR. The role of AMPK was probed using compound C, an AMPK inhibitor and AMPKα1/2 shRNA to knockdown AMPK gene. SHHF and Sprague-Dawley control rats were treated with the stilbenoids (2.5mg/kg/day) by oral gavage. Baseline and endpoint echocardiography were performed to capture cardiac function and heart dimensions. Gnetol inhibited all markers of hypertrophy. Pterostilbene inhibited myocyte size augmentation and protein synthesis but did not prevent fetal gene expression. Gnetol and pterostilbene activated AMPK. Indeed, pre-treatment with compound C and genetic knockdown of AMPK abolished the ability of gnetol and pterostilbene to inhibit myocyte growth. While MITF expression increased in response to ET-1, pre-treatment with stilbenoids prevented ET-1-induced MITF expression. Gnetol and pterostilbene inhibited cardiomyocyte hypertrophy in vitro, at least in part, via AMPK activation. Although the stilbenoids did not prevent left ventricular hypertrophy in SHHF rat, they improved diastolic function to the same extent despite differences in their bioavailabilities. Thus, further studies on mechanisms of cardioprotective effects of stilbenoid polyphenols are warranted.