Responses to IFN-γ are mediated through signal transducer and activator of transcription-1 and several so-called interferon response factors (IRFs) (8–10), especially IRF-7 and IRF-9 (1), whereas IL-4 and IL-13 activate STAT-6 (11) and IRF-4 (1). Consequently, IFN-γ and IL-4 provoke widely different transcriptional responses, effectively defining their divergent phenotypes (12). Moreover, the ability of IFN-γ to downregulate many IL-4-induced genes [for example cluster E vs F of reference (12) and module 15 of reference (1)] amplifies these phenotypic differences. Participation of epigenetic mechanisms in macrophage polarization has also been demonstrated (13). In particular, the ability of IFN-γ or IL-4 to alter the local histone code, which determines whether the relevant transcription factors have access to promoter sequences, has been implicated in their ability to drive cells toward different phenotypes (14–17). However, knowledge regarding the role of specific histone-modifying enzymes is presently fragmentary and sometimes conflicting (13). We, therefore, took an unbiased approach by using an RT-qPCR array of 84 epigenetic regulators to investigate the impact of IFN-γ and IL-4, singly and in combination (to look for antagonistic effects) on human primary macrophages. We identified 11 genes up- or downregulated by the cytokines but some of these were affected, at least in part, secondary to inhibition of cell proliferation. Lysine demethylase 6B (KDM6B) was the only putative activator of transcription that was upregulated by both IFN-γ and IL-4, thereby implying a functional role in promoting gene expression by both cytokines. To investigate this hypothesis directly, the functional consequences of inhibiting and silencing KDM6B were investigated further.