The development of statistical tests of natural selection at the DNA level in population samples has been ongoing for the past 13 years. The current state of the field is reviewed, and the available tests of selection are described. All tests use predictions from the theory of neutrally evolving sites as a null hypothesis. Departures from equilibrium-neutral expectations can indicate the presence of natural selection acting either at one or more of the sites under investigation or at a sufficiently tightly linked site. Complications can arise in the interpretation of departures from neutrality if populations are not at equilibrium for mutation and genetic drift or if populations are subdivided, both of which are likely scenarios for humans. Attempts to understand the nonequilibrium configuration of silent polymorphism in human mitochondrial DNA illustrate the difficulty of distinguishing between selection and alternative demographic hypotheses. The range of plausible alternatives to selection will become better defined, however, as additional population genetic data sets become available, allowing better null models to be constructed.