Improvements in workflow and chemistry continue to provide unprecedented throughput and accuracy from sequencing by synthesis systems, yet have increased demand for more sensitive and extensible methods at all stages of analysis from basecalling through variant prediction. In particular, the methods underlying somatic variant prediction from matched tumor/normal samples have significantly progressed as these results see greater potential for clinical application. This presentation describes recent innovations in Illumina sequencing, primary analysis and variant calling methods which contribute to somatic variant discovery in cancer samples.