Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive primary cutaneous lymphoma characterized by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA) also known as CD123. In addition to several therapies currently undergoing clinical trials, Tagraxofusp-erzs (Stemline Therapeutics, Inc., NY) is a single FDA-approved option available for treatment of adults and children over 2 years of age suffering from BPDCN. It was designed to target CD123 overexpression in BPDCN as a CD123-directed cytotoxin consisting of a recombinant human interleukin-3 fused to a truncated diphtheria toxin. We discuss a case of a male patient in his late 70s’ who presented with an asymptomatic rash involving the back and the right knee that initially developed as pink patches, progressed into plaques, and subsequently rapidly evolved into a tumor involving the right knee that was confirmed as BPDCN on skin biopsy and was accompanied by bone marrow involvement. Upon initiation of first line tagraxofusp-erzs therapy, the patient did not achieve improvement. However, off-label use of venetoclax (AbbVie Inc, IL and Genentech-USA, CA), a Bcl2 inhibitor currently in a Phase I clinical trial, resulted in a satisfactory clinical outcome, nearly complete resolution of a right knee tumor lesion, and deferment of bone marrow transplant. We believe that our case exemplifies the complexity of BPDCN, briefly reviews current treatment and management options that are only in their infancy and raises awareness towards success with alternative off-label therapies such as venetoclax when treating BPDCN. J Drugs Dermatol. 20(5):550-551. doi:10.36849/JDD.5373.