The future NSD1 research agenda should aim to (i) mechanistically determine the gene dosage–phenotype correlation in germline syndromes with aberrant NSD1 activity, (ii) identify the cellular and molecular mechanisms of malignant transformation by altered NSD1 activity (mutations, epigenetic silencing), and (iii) optimize and validate small molecule NSD1-SET inhibitors for therapy of pediatric AML, driven by the NUP98-NSD1 fusion gene, and research for strategies to selectively interfere in situations when reduced NSD1 activity is the driving force. Here, NUP98 is linked to acute myeloid leukemia.