Histone methyl-transferases (HMTs) are key enzymes that post-translationally methylate nuclear histone proteins and play critical roles in gene expression, epigenetic regulation and diseases in eukaryotic organisms. Mixed lineage leukemias (MLLs) are human HMTs that specifically methylate histone H3 at lyisine-4 and regulate gene activation. MLLs are also well known to be rearranged often in acute myeloid and lymphoid leukemias. Human encodes several MLLs that have similar enzymatic activities but diverse functions. Herein, we have reviewed the recent advances in understanding the diverse functions of MLL family of HMTs in gene regulation, hormone signaling and cell cycle regulation in human.