Myeloid malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are a heterogeneous group of disorders that share a common biology and are a major source of morbidity and mortality. In the last several years, studies using next-generation sequencing (NGS) have identified a core set of recurrently mutated myeloid malignancy genes in the majority of patients with AML and MDS, including those with normal cytogenetics. DNA-level mutations in several of these genes including NPM1, FLT3, and CEBPA in AML and ASXL1, ETV6, EZH2, RUNX1, and TP53 in MDS are associated with changes in patient outcomes and are now tested for in clinical laboratories. In addition to providing prognostic information, these gene mutations can be used to monitor patient disease burden through the use of ultrasensitive detection techniques. In this review, we will focus on the clinical utility of various NGS-based methods including whole-genome sequencing, exome sequencing, and targeted panel-based sequencing in the initial diagnosis and management of AML and MDS and cover recent methodological advances for the molecular monitoring of AML and MDS.