Our understanding of the genetics of acute myeloid leukemia (AML) development from myelodysplastic syndrome (MDS) has advanced significantly due to next-generation sequencing technology. While differences in cell biology and maturation exist between MDS and AML secondary to MDS, these two diseases are genetically related. MDS and secondary AML cells harbor mutations in many of the same genes and functional categories, including chromatin modification, DNA methylation, RNA splicing, cohesin complex, transcription factors, cell signaling, and DNA damage, confirming they are a disease continuum. Differences in the frequency of mutated genes in MDS and secondary AML indicate that the order of mutation acquisition is not random during progression. In almost every case, disease progression is associated with clonal evolution, typically defined by the expansion or emergence of a subclone with a unique set of mutations. Monitoring tumor burden and clonal evolution using sequencing provides advantages over using the blast count, which underestimates tumor burden, and could allow for early detection of disease progression prior to clinical deterioration. In this review, we outline advances in the study of MDS to secondary AML progression, with a focus on the genetics of progression, and discuss the advantages of incorporating molecular genetic data in the diagnosis, classification, and monitoring of MDS to secondary AML progression. As sequencing is becoming routine in the clinic, ongoing research is needed to define the optimal assay to use in different clinical situations and how the data can be used to improve outcomes for patients with MDS and secondary AML.