Recent advances in next generation sequencing have greatly enhanced the scope and speed of genomic cancer research. Apart from merely listing identified mutations from cancer genomes sequencing, this review will summarize some insights specifically focusing on the biology of allele generating cancer driver mutations and clonal patterns during tumor evolution. Studies using massively parallel sequencing of primary tumor samples and cancer cell lines have identified neomorphic alleles and other recurrent mutations in proteins involved in chromatin modification and in the regulation of transcription and translation. Further studies with deep sequencing of matched primary and metastatic tumors have also started to characterize distinct patterns of tumor clonal evolution. The development of single cell sequencing is expected to help further elucidate tumor clonality and aid the translation of these discoveries into diagnostic and therapeutic applications.