Next generation sequencing heralds the promise of being a one-stop shop for the technological needs in genomic exploration. In this presentation, some of the methodological challenges in transcriptome sequencing and methylation analysis using NG sequencing are explored. Firstly, using publicly available data from the 1000 genomes project, technology-specific error signatures are explored using an entropy-based statistical framework. Estimates of the false discovery rate for novel variants and for the accuracy of allele calls are derived. This accuracy of allele calls has strong implications for the analysis of allelic imbalance, which may be a promising approach for the interpretation of genomic alterations in cancer using the intermediate RNA phenotype. Lastly, a targeted pipeline for methylation analysis using droplet-based PCR-enrichment is presented.