The ideal fluorescent probe for live-cell imaging is bright and non-cytotoxic and can be delivered easily into the living cells in an efficient manner. The design of synthetic fluorophores having all three of these properties, however, has proved to be challenging. Here, we introduce a simple, yet effective, strategy based on well-established chemistry for designing a new class of fluorescent probes for live-cell imaging. A box-like hybrid cyclophane, namely ExTzBox·4X (6·4X, X = PF6-, Cl-), has been synthesized by connecting an extended viologen (ExBIPY) and a dipyridyl thiazolothiazole (TzBIPY) unit in an end-to-end fashion with two p-xylylene linkers. Photophysical studies show that 6·4Cl has a quantum yield ΦF = 1.00. Furthermore, unlike its ExBIPY2+ and TzBIPY2+ building units, 6·4Cl is non-cytotoxic to RAW 264.7 macrophages, even with a loading concentration as high as 100 μM, presumably on account of its rigid box-like structure which prevents its intercalation into DNA and may inhibit other interactions with it. After gaining an understanding of the toxicity profile of 6·4Cl, we employed it in live-cell imaging. Confocal microscopy has demonstrated that 64+ is taken up by the RAW 264.7 macrophages, allowing the cells to glow brightly with blue laser excitation, without any hint of photobleaching or disruption of normal cell behavior under the imaging conditions. By contrast, the acyclic reference compound Me2TzBIPY·2Cl (4·2Cl) shows very little fluorescence inside the cells, which is quenched completely under the same imaging conditions. In vitro cell investigations underscore the significance of using highly fluorescent box-like rigid cyclophanes for live-cell imaging.