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Evaluation of: Kimchi-Sarfaty C, Oh JM, Kim IW et al.: A 'silent' polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525-528 (2007) [1] . Individuals carrying silent SNPs in the MDR1 gene encoding P-glycoprotein sometimes reveal altered P-glycoprotein pharmacokinetics. There is no rational explanation for why silent SNPs might have such effects, especially when no change in P-glycoprotein mRNA and protein expression levels has been observed. The purpose of this study was to perform careful ex vivo (in cells) analysis of the effects of the three polymorphisms (C1236T, G2677T C3435T) on P-glycoprotein expression and activity. As a result, it has been shown that silent polymorphisms (in particular, C3435T) in MDR1 can alter P-glycoprotein conformation and protein activity/substrate specificity. This study is of immense importance as it demonstrates for the first time that naturally occurring silent SNPs can lead to the synthesis of protein product with the same amino acid sequence but different structural and functional properties. Thus, silent SNPs should no longer be neglected in determining the likelihood of development of various diseases, and should be taken into account in personalized drug treatment and development programs.