Depicted as playing cards belonging to the same suit, the paralogous MLL3 and MLL4 lysine methyltransferase (KMT) complexes share a common set of core and auxiliary subunits as well as similar histone methylase functions. On each card, largely divergent processes are described on opposing sides – highlighting the potential capacity of these KMT complexes to participate in both tumor-supportive and tumor-suppressive mechanisms. To understand how MLL3 and MLL4 can regulate such diverse and sometimes contrasting processes, read more in this review article by Wang and colleagues (pp. 1041–1054). Cover artwork created by Marvin Aberin with Biorender.com.