Rapid advances in DNA sequencing improve existing techniques and enable new approaches in genetics and functional genomics, bringing about unprecedented coverage, resolution and sensitivity. Enhanced toolsets can facilitate the untangling of connections between genomic variation, environmental factors and phenotypic effects, providing novel opportunities, but may also pose challenges in data interpretation, especially in highly heterogeneous human populations. Laboratory rodent strains, however, offer a variety of tailored model systems with controlled genetic backgrounds, facilitating complex genotype/phenotype relationship studies. In this review we discuss the advent of massively parallel sequencing, its methodological advantage for molecular analysis in model organisms and the expectation of increased understanding of biologically relevant consequences of human genetic variation.