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The information that determines our genetic make-up – from our eye color to our propensity to get cancer or genetic diseases – is encoded in the DNA sequence of our genomes. This DNA information is interpreted by proteins called transcription factors that ‘read’ the four-letter code in our DNA, promoting the activation or repression of genetic programs. Unfortunately, we have been unable to decipher the non-protein-coding portion of our genomes, which comprises >95% of our DNA, even though we now have access to thousands of fully sequenced human genomes and the numbers are increasing daily. A fundamental problem of modern biology will be how to discern DNA differences between people that affect our physical differences and the manifestation of disease. As a result, a major challenge facing computational and structural biologists is to crack the DNA code that will allow us to understand the impact of DNA differences on protein-DNA interactions and gene expression. The solution to this challenge will likely come from the convergence of theoretical, computational, biophysical, and structural approaches. The BIRS format is ideal for bringing together this combination of scientists in an informal and collaborative setting to further advance this goal.