In the last twenty years the efforts in interfacing neurons to artificial devices played an important role in understanding the functioning of neuronal circuity. As result, this new brain technology opened new perspectives in several fields as neuronal basic research and neuro-engineering. Nowadays it is well established that the functional, bidirectional and real-time interface between artificial and neuronal living systems counts several applications as the brain-machine interface, the drug screening in neuronal diseases, the understanding of the neuronal coding and decoding and the basic research in neurobiology and neurophysiology. Moreover, the interdisciplinary nature of this new branch of science has increased even more in recent years including surface functionalisation, surface micro and nanostructuring, soft material technology, high level signal processing and several other complementary sciences. In this framework, Micro-Electrode Array (MEA) technology has been exploited as a powerful tool for providing distributed information about learning, memory and information processing in cultured neuronal tissue, enabling an experimental perspective from the single cell level up to the scale of complex biological networks. An integral part in the use of MEAs involves the need to apply a local stimulus in order to stimulate or modulate the activity of certain regions of the tissue. Currently, this presents various limitations. Electrical stimulation induces large artifacts at themost recording electrodes and the stimulus typically spreads over a large area around the stimulating site. Compound optical uncaging is a promising strategy to achieve high spatial control of neuronal stimulation in a very physiological manner. Optical uncaging method was developed to investigate the local dynamic responses of cultured neurons. In particular, flash photolysis of caged compounds offers the advantage of allowing the rapid change of concentration of either extracellular or intracellular molecules, such as neurotransmitters or second messengers, for the stimulation or modulation of neuronal activity. This approach could be combined with distributed MEA recordings in order to locally stimulate single or few neurons of a large network. This confers an unprecedented degree of spatial control when chemically or pharmacologically stimulating complex neuronal networks. Starting from this point, the main objective of this chapter is the discussion of an integrated solution to couple the method based on optical stimulation by caged compounds with the technique of extracellular recording by using MEAs. 7