VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a novel entity manifesting with a multiplicity of clinical features. Somatic mutations of the UBA1 gene in hematopoietic stem cells constitute the genetic basis of VEXAS. As an X-linked disorder, most cases occur in men, classically developing symptoms during the fifth to sixth decade of life. Considering its multidisciplinary nature involving numerous branches of internal medicine, VEXAS has elicited a wide medical interest and several medical conditions have been associated with this disease. Even so, its recognition in everyday clinical practice is not necessarily straightforward. Close collaboration between different medical specialists is mandatory. Patients with VEXAS may manifest a range of features from manageable cytopenias to disabling and life-threatening autoimmune phenomena with limited responses to therapy, with the potential for progression to hematological malignancies. Diagnostic and treatment guidelines are exploratory and include a range of rheumatological and supportive care treatments. Allogeneic hematopoietic stem cell transplantation is potentially curative, but its risks are significant and its position in the treatment algorithm is yet to be defined. Herein, we present the variegated manifestations of VEXAS, provide practice criteria for diagnostic testing of UBA1, and discuss potential treatment options, including allogeneic hematopoietic stem cell transplantation, current evidence, and future directions.