Bromodomain and extraterminal motif (BET) proteins are promising therapeutic targets in cancer and pharmacologic inhibitors have entered clinical testing. BET inhibitors competitively target the bromodomain-acetyl lysine interaction and remove BETs from chromatin. However, BET inhibitors induce selective effects on transcription, making it difficult to predict which genes and which diseases may respond to therapeutic targeting, and suggesting that BETs may exert complex regulatory influence beyond transcriptional activation. Importantly, these inhibitors do not distinguish between BET family members, and the specific functions of BRD2, BRD3, and BRD4 are comparatively poorly understood. By examining the occupancy patterns of BRD2, BRD3, and BRD4 genome-wide we define an association between BRD2 and the architectural/insulator protein CCCTC-binding factor (CTCF). Using a combination of locus-specific genome editing and global BRD2 depletion we show that both CTCF and BRD2 are required to maintain a boundary element that separates the regulatory apparatus of two adjacent genes. CTCF’s role as a boundary factor may be linked to its function in organizing chromatin architecture. Loss of BRD2 allowed increased interactions to occur across architectural domain boundaries specifically occupied by BRD2 genome-wide. These observations indicate that BRD2 is required to potentiate the boundary function of CTCF, and link the BET family of chromatin readers to the maintenance of 3-D genome architecture. BETs contain highly conserved domains, yet to what degree they can functionally replace one another has not been well characterized. Overexpression of BRD3 partially rescued the transcriptional effects of BRD2 loss, while overexpression of BRD4 was less able to compensate. To directly compare BET function at a defined location, we developed a tethering system to target individual BET proteins to an endogenous BET-dependent gene. Forced tethering of BRD4, but not BRD2 or BRD3, partially restored BET inhibitor-induced transcriptional silencing. Taken together, the work described here highlights functional and mechanistic distinctions between BET family members, and suggests that the response to BET inhibition may be viewed as a consequence of targeting both divergent and partially redundant roles of individual BETs in transcriptional regulation and chromatin architecture.