Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.