Ecotropic virus integration site-1 (EVI1)-rearranged acute myeloid leukemia (AML) joins the club of ERG-dependent alterations and cancers. In this issue of Blood, Schmoellerl et al have studied 2 EVI1-driven human and murine leukemia models (EVI1^High). They showed that EVI1 binds and regulates the open chromatin state at the ERG gene, leading to high expression of this E-twenty six (ETS) transcription factor. ERG enforces an oncogenic program, including self-renewal and survival properties associated with hematopoietic differentiation blockade. Some of the other genetic alterations and human cancers associated with high ERG expression or dependency are indicated on the right side, including different molecular subgroups of AML, B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), Ewing sarcoma, and prostate cancer. MLL, mixed lineage leukemia; RUNX1, runt-related transcription factor 1.