Mutations are the driving molecular causes of various biological processes such as developmental and cancer. Recent findings of genomic heterogeneity among ostensibly homogeneous cell populations such as cancer cells demand genomic characterization of mutations at the individual cell level to better understand the underlying biology. Additionally, single cell technologies make genomic analysis feasible for the characterization of rare cells such as circulating tumor cells. Due to its high sensitivity, next generation sequencing (NGS) represents the ideal technology to analyze a collection of mutations in single cells. The challenge, however, is that single cells yield limited amounts of DNA, that need to be amplified prior to NGS. To overcome this challenge, whole genome amplification (WGA), coupled with multiplex PCR-based targeted enrichment, were tested for mutation detection in single cells isolated from two colon cancer cell lines, Lovo and HT29.