Local interactions between (bio)chemicals and biological interfaces play an important role in fields ranging from surface patterning to cell toxicology. These interactions can be studied using microfluidic systems that operate in the "open space", that is, without the need for the sealed channels and chambers commonly used in microfluidics. This emerging class of techniques localizes chemical reactions on biological interfaces or specimens without imposing significant "constraints" on samples, such as encapsulation, pre-processing steps, or the need for scaffolds. They therefore provide new opportunities for handling, analyzing, and interacting with biological samples. The motivation for performing localized chemistry is discussed, as are the requirements imposed on localization techniques. Three classes of microfluidic systems operating in the open space, based on microelectrochemistry, multiphase transport, and hydrodynamic flow confinement of liquids are presented. Space, the final frontier? Microfluidic technologies for controlling liquid dispensing and handling will become central for localizing (bio)chemical reactions/functions on biological interfaces. However, microfluidic systems must then operate in the "open space", that is, without the sealed channels and chambers commonly used (see picture). The development of such open-space microfluidic technologies is reported. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.