The process of identifying genomic sites that show statistical relationships to phenotypes holds great promise for human health and disease (Hindorff et al. 2009). However, our current inability to efficiently interpret noncoding variants impedes progress toward using personal genomes in medicine. Coordinated efforts to survey the noncoding genome have shown that sequences marked by DNA accessibility and certain histone modifications are enriched for variants that are statistically related to phenotypes (The ENCODE Project Consortium 2012; Roadmap Epigenomics Consortium et al. 2015). The first stages of a mechanistic hypothesis can now be assigned to variants that directly overlap these annotations (Fu et al. 2014; Kircher et al. 2014; Ritchie et al. 2014). However, simply considering the overlap of a variant with annotations underutilizes these data; more can be extracted by understanding the DNA–protein interactions as a function of the underlying sequence. Proteins that recognize specific signals in the DNA influence its accessibility and histone modifications (Voss and Hager 2014). Given training data, models parameterized by machine learning can effectively predict protein binding, DNA accessibility, histone modifications, and DNA methylation from the sequence (Das et al. 2006; Arnold et al. 2013; Benveniste et al. 2014; Pinello et al. 2014; Lee et al. 2015; Setty and Leslie 2015; Whitaker et al. 2015). A trained model can then annotate the influence of every nucleotide (and variant) on these regulatory attributes. This upgrades previous approaches in two ways. First, variants can be studied at a finer resolution; researchers can prioritize variants predicted to drive the regulatory activity and devalue those predicted to be irrelevant bystanders. Second, rare variants that introduce a gain of function will often not overlap regulatory annotations in publicly available data. An accurate model for regulatory activity can predict the gain of function, allowing follow-up consideration of the site. In recent years, artificial neural networks with many stacked layers have achieved breakthrough advances on benchmark data sets in image analysis (Krizhevsky et al. 2012) and natural language processing (Collobert et al. 2011). Rather than choose features manually or in a preprocessing step, convolutional neural networks (CNNs) adaptively learn them from the data during training. They apply nonlinear transformations to map input data to informative high-dimensional representations that trivialize classification or regression (Bengio et al. 2013). Early applications of CNNs to DNA sequence analysis surpass more established algorithms, such as support vector machines or random forests, at predicting protein binding and accessibility from DNA sequence (Alipanahi et al. 2015; Zhou and Troyanskaya 2015). More accurate models can more precisely dissect regulatory sequences, thus improving noncoding variant interpretation. However, to fully exploit the value of these models, it is essential that they are technically and conceptually accessible to the researchers who can take advantage of their potential. Here, we introduce Basset, an open source package to apply deep CNNs to learn functional activities of DNA sequences. We used Basset to simultaneously predict the accessibility of DNA sequences in 164 cell types mapped by DNase-seq by the ENCODE Project Consortium and Roadmap Epigenomics Consortium (The ENCODE Project Consortium 2012; Roadmap Epigenomics Consortium et al. 2015). From these data sets, CNNs simultaneously learn the relevant sequence motifs and the regulatory logic with which they are combined to determine cell-specific DNA accessibility. We show that a model achieving this level of accuracy provides meaningful, nucleotide-precision measurements. Subsequently, we assign Genome-wide association study (GWAS) variants cell-type–specific scores that reflect the accessibility difference predicted by the model between the two alleles. These scores are highly predictive of the causal SNP among sets of linked variants. Importantly, Basset puts CNNs in the hands of the genome biology community, providing tools and strategies for researchers to train and analyze models on new data sets. In conjunction with genomic big data, Basset offers a promising future for understanding how the genome crafts phenotypes.