In the last few years, the biomedical field has experienced a revolution thanks to the development of Next Generation Sequencing (NGS). Now we can obtain the complete genetic information of a person and analyse how this information is being used in a few days and with a limited cost. NGS is commonly used to identify the inherited clonal mutations present in patients, however the identification of the genetic heterogeneity within a cellular population remains still challenging. Genetic heterogeneity has long been proposed to be an intrinsic driver of cancer initiation and progression. The appearance of mutations is important for the development of drug resistance clones and therefore constitutes a major factor in cancer relapse. As human cancers exhibit extreme levels of genetic heterogeneity (Lawrence et al. 2013), we need to develop methods able to resolve subclonal mutations. Single-cell sequencing approaches are able to resolve such complexity, however their cost and technical complexity makes them impractical for their clinical use. We are developing novel simple and affordable approaches able to confidently detect mutations that are present in less than 1% of the cells. We are also trying to resolve complex structural variations of clinical relevance for cancer genotyping. We will benchmark our novel genotyping approaches with current standards in Clinical Genomics.