While recent advances in DNA sequencing have revolutionized clinical genetics, substantial challenges remain. Among the most pressing challenges are reliably and affordably discovering disease-causing variation in patients, and accurately interpreting the functional effects of detected variation. It is now possible to sequence whole human genomes in a matter of days, and at a cost of thousands of dollars. As a result, there has been a staggering accumulation of sequence data from healthy and affected individuals. However, we currently lack generally applicable methods for interpreting the functional consequences of variation. As long as this problem remains unsolved, we will be unable to realize the full potential of constantly advancing DNA sequencing technologies.