A gene fragment corresponding to the region of difference-1 (RD-1) of the Mycobacterium tuberculosis genome, spanning open reading frames Rv3871 to Rv3879c, is missing in all bacillus Calmette–Guerin (BCG) vaccine strains of M. bovis, indicating that this was perhaps the primary deletion event responsible for attenuation of virulent M. bovis. The RD-1 locus has, therefore, been considered crucial in the pathogenesis of M. tuberculosis. Two most predominant secretory proteins encoded by this region viz. CFP-10 (Rv3874) and ESAT-6 (Rv3875) are being widely evaluated as candidate vaccine(s) and used as antigens in the diagnosis of tuberculosis. However, several recent reports have implicated their putative role in deactivation of the macrophage and dendritic cell functions. A large body of recent literature provides an inkling of various mechanisms these proteins might use to down regulate normal macrophage functions and their possible contribution to virulence of M. tuberculosis. This review re-emphasizes the suggestion about the dual function of these two secreted mycobacterial proteins, viz., they have both T-cell activation and macrophage deactivation functions.