Detecting biases in biological patterns and processes is central to life science inquiry, but since unambiguous signatures of directionality are often elusive, it is also a source of methodological frustration. Increasingly sophisticated experimental and theoretical tools have been marshaled in the areas of genomics, phylogenetics, and evolutionary paleobiology, but new statistical models and model systems are needed to isolate signals from noise in large data sets. Concerted effort by multidisciplinary teams working on the details of mutational processes, genomic signatures, and macroevolutionary trends help to orient future research with robust procedures that identify directionality in lineages, both past and present, thereby advancing our understanding of evolutionary dynamics within and across populations and lineages.