A holy grail of genetics is to decipher the mapping from genotype to phenotype. Recent advances in sequencing technologies allow the efficient genotyping of thousands of individuals carrying a particular phenotype in an effort to reveal its genetic determinants. However, the interpretation of these data entails tackling significant statistical and computational problems that stem from the complexity of human phenotypes and the huge genotypic search space. Recently, an alternative pathway-level analysis has been employed to combat these problems. In this review we discuss these developments, describe the challenges involved and outline possible solutions and future directions for improvement.