Accurately mapping RNA-Seq reads to the reference genome is a critical step for performing downstream analysis such as transcript assembly, isoform detection and quantification. Many tools have been developed, however, given the huge size of the next generation sequencing datasets and the complexity of the transcriptome, RNA-Seq read mapping remains a challenge with the ever-increasing amount of data. We develop Omicsoft sequence aligner (OSA), a fast and accurate alignment tool for RNA-Seq data. Benchmarked with existing methods, OSA improves mapping speed 4-10-fold with better sensitivity and less false positives.