The completion of Human Genome Project established a base line for human genome reference sequence allowing characterization of various alterations underlying several human diseases, including cancer, and has brought the field of genomics to this unprecedented moment of a great scientific ferment. It also sparked a concomitant revolution in sequencing technologies that has become a fundamental tool for genome analysis with potential to transform medical practice. As an emerging field, the next-generation sequencing technologies has stimulated rapid cataloging of all alterations in cancer genomes and has enabled researchers to look at large-scale genome events such as chromosomal lesions and copy-number variations as well as small-scale aberrations represented by point mutations, small insertions and deletions. Several technological advancements with smaller, faster versions of available technologies have recently been introduced, though remains to be validated. Here, we review the application of next generation sequencing technology in understanding the underlying goal to catalog of human cancer-causing somatic mutations.