The diffuse use of Next Generation Sequencing (NGS) is having a tremendous impact on the way we approach our diagnostic work up on tumour diagnosis, and, if on one hand it is always exciting receiving novel gene fusions or mutations, on the other hand the question is “Can we predict on morphology?”. Certainly, there are categories of tumours in which we can suggest a morphological diagnosis and one is the category of Undifferentiated Small Round Cell Sarcoma (USRCS) other than Ewing’s sarcoma (ES). In the past, these tumour morphologically similar to ES but without the canonical EWSR1 gene rearrangement, were called “Atypical ES” or USRCS, NOS. Now, sarcomas with CIC, BCOR and NFATC2 gene rearrangements are amongst the new entities more likely to be suggested on morphological ground. Another emerging group of tumour with reproducibile morphological features are the GLI-associated tumours. These are locally aggressive tumours characterised by a multinodular growth pattern, nested architecture, rich vascular background and epithelioid morphology. EWSR1::SMAD3 positive fibroblastic tumour is a benign neoplasm of superficial soft tissue, especially hands and feet, showing a zonation pattern with intersecting fascicles of fibroblastic spindle cells with a diffuse ERG positivity on immunohistochemistry. An important group of neoplasia with reproducible morphology and immunoprofile is the NTRK-rearranged mesenchymal tumour with their peculiar stromal and perivascular hyalinisation. This is an important group to recognize because they can be targeted with kinase-inhibitor. Finally, another emerging group of tumours that can be suspected before sending out to the Lab, is the KMT2A rearranged sarcoma. These are a group of aggressive, deep soft tissue tumour that resemble sclerosing epithelioid fibrosarcoma, but MUC4 negative and frequent cyclin D1 positivity. The use of NGS as diagnostic tools is bringing an enormous amount of new data and therefore, new exciting challenges facing our daily practice.