As size, weight, and performance demands drive electronics packages to become increasingly thinner and more compact, volume restrictions prevent the use of large intermediate heat spreaders to mitigate heat generation non-uniformities. Instead, these non-uniform heat flux profiles are imposed directly on the ultimate heat sink, either due to chip-scale variations or the desire to cool multiple discrete devices. A better understanding of the impacts of non-uniform heating on two-phase flow characteristics and thermal performance limits for microchannel heat sinks is needed to address these thermal packaging trends. An experimental investigation is performed to explore flow boiling phenomena in a microchannel heat sink with point hotspots, as well as non-uniform streamwise and transverse heating conditions across the entire heat sink area. The investigation is conducted using a silicon microchannel heat sink with a 5 × 5 array of individually controllable heaters attached to a 12.7 mm × 12.7 mm square base. The channels are 240 μm wide, 370 μm deep, and separated by 110 μm wide fins. The working fluid is FC-77, flowing at a mass flux of approximately 890 kg/m2s. High-speed visualizations of the flow are recorded to observe the local flow regimes. It is found that even though the substrate thickness beneath the microchannels is very small (200 μm), significant lateral conduction occurs and must be accounted for in the calculation of the local heat flux imposed. For non-uniform heat input profiles, with peak heat fluxes along the central streamwise and transverse directions, it is found that the local flow regimes, heat transfer coefficients, and wall temperatures deviate significantly from a uniformly heated case. These trends are assessed as a function of an increase in the relative magnitude of the nonuniformity between the peak and background heat fluxes.