In the past few years, we have experienced a paradigm shift in human genetics. Accumulating lines of evidence have highlighted the pivotal role of rare genetic variations in a wide variety of traits and diseases. Studying rare variations is a needle in a haystack problem, as large cohorts have to be assayed in order to trap the variations and gain statistical power. The performance of DNA sequencing is exponentially growing, providing sufficient capacity to profile an extensive number of specimens. However, sample preparation schemes do not scale as sequencing capacity. A brute force approach of preparing hundredths to thousands of specimens for sequencing is cumbersome and cost-prohibited. The next challenge, therefore, is to develop a scalable technique that circumvents the bottleneck in sample preparation. My tutorial will provide background on rare genetic variations and DNA sequencing. I will present our sample prep strategy, called DNA Sudoku, that utilizes combinatorial pooling/compressed sensing approach to find rare genetic variations. More importantly, I will discuss several major distinction from the classical combinatorial due to sequencing specific constraints.