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Simple Summary: Pathogenic germline variants affecting RUNX1 are associated with qualitative and/or quantitative platelet defects, and predispose to hematologic malignancies. The latter manifests in approximately 44% of carriers and can occur from early childhood to late adulthood. In addition to the predisposing RUNX1 germline variant, the acquisition of somatic genetic alterations is presumed to drive leukemic transformation in an inflammatory bone marrow niche. The spectrum of somatic mutations occurs heterogeneously between individuals, even within families, and there is no clear genotype–phenotype correlation. In this review, we summarize previously published patients harboring (likely) pathogenic RUNX1 germline alterations in whom somatic alterations were additionally analyzed. We provide an overview of their phenotypes and the most frequent somatic genetic alterations. Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia. [ABSTRACT FROM AUTHOR]