DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.