Advantages of performing analytical and diagnostic tasks in microfluidic-based systems include small sample volume requirements, rapid transport times and the promise of compact, portable instrumentation. The application of such systems in home and point-of-care situations has been limited, however, because these devices typically require significant associated hardware to initiate and control fluid flow. Capillary-based pumping can address many of these deficiencies by taking advantage of surface tension to pull fluid through devices. The development of practical instrumentation however will rely upon the development of precision control schemes to complement capillary pumping. Here, we introduce a straightforward, robust approach that allows for reconfigurable fluid guidance through otherwise fixed capillary networks. This technique is based on the opening and closing of microfluidic channels cast in a flexible elastomer via automated or even manual mechanical actuation. This straightforward approach can completely and precisely control flows such as samples of complex fluids, including whole blood, at very high resolutions according to real-time user feedback. These results demonstrate the suitability of this technique for portable, microfluidic instruments in laboratory, field or clinical diagnostic applications.