Detection of somatic mutations holds great potential in cancer treatment and has been a very active research field in the past few years, especially since the breakthrough of the next-generation sequencing technology. A collection of variant calling pipelines have been developed with different underlying models, filters, input data requirements, and targeted applications. This review aims to enumerate these unique features of the state-of-the-art variant callers, in the hope to provide a practical guide for selecting the appropriate pipeline for specific applications. We will focus on the detection of somatic single nucleotide variants, ranging from traditional variant callers based on whole genome or exome sequencing of paired tumor-normal samples to recent low-frequency variant callers designed for targeted sequencing protocols with unique molecular identifiers. The variant callers have been extensively benchmarked with inconsistent performances across these studies. We will review the reference materials, datasets, and performance metrics that have been used in the benchmarking studies. In the end, we will discuss emerging trends and future directions of the variant calling algorithms.