One promise of personalized medicine is that it will be possible to make useful predictions about the phenotypes of individuals from their complete genome sequences (e.g. concerning their susceptibility to disease). However, to what extent is knowledge about an individual's genotype, together with information about the environment that they have experienced, sufficient to predict phenotypic variation? In the present review, we argue that, although the 'typical' phenotypic outcome of an individual's genome can be predicted, it is much more difficult to predict the actual outcome for a particular individual. We highlight three reasons for this. First, the outcome of mutations can be influenced by random (stochastic) processes. Second, genetic variation present in one generation can influence phenotypic traits in the next generation, even if individuals do not inherit this variation. Third, the environment experienced by one generation can influence phenotypic variation in the next generation. These contributions to phenotypic variation have long been appreciated by quantitative geneticists, although they have only recently been studied at the molecular level. Taken together, they mean that, in many cases, the genotypes of individuals and the environment that they experience may not be sufficient to determine their phenotypes. A more comprehensive genotype-to-phenotype model will be required to make accurate predictions about the biology of individuals. What determines the phenotype of an individual? In this review we highlight recent mechanistic studies dissecting why the phenotypes of individuals cannot always be reliably predicted from their genotypes. This includes understanding the consequences of stochastic noise, parental non-inherited mutations, and trans-generational effects of the environment © 2012 The Authors Journal compilation © 2012 FEBS.