Detection of individual molecules and identification of extremely rare variant alleles within complex samples are becoming increasingly relevant in many areas of clinical and basic research. The limitations of most available technologies are that they lack the required sensitivity and specificity. Hence, we have developed several approaches that enable analysis of individual DNA/RNA molecules that can be applied to various types of samples, including single cells and liquid biopsies. Currently, we are developing tools that enable analyses of short and highly fragmented DNA/RNA molecules as well as their modifications. We are applying our techniques to sarcomas identifying biomarkers and understanding tumor development.