Our recent studies have utilized a combination of genome-wide and genetic approaches to define the molecular mechanisms that underlie the development of classically activated and alternatively activated macrophage phenotypes. These studies suggest a relatively simple model of hierarchical interactions between lineage-determining and signal-dependent transcription factors that are required to select functional cis-active regulatory elements. The majority of these interactions occur at enhancer-like elements that are distant from target promoters. The discovery that these enhancer elements themselves generate transcripts referred to as ‘eRNAs’ raises a number of interesting new questions regarding the mechanisms underlying enhancer function and therapeutic approaches to modulate macrophage phenotypes.