Real-time closed-loop technology is being advanced by several other groups, with their own custom systems. Fetz and co-workers used single-electrode extracellular recordings in the monkey cortex to trigger single-electrode stimulation, which induced plasticity that altered functional connectivity and motor behavior. This was carried out with a custom wireless stimulation and recording setup (Jackson et al., 2006). Venkatraman et al. (2009) wrote custom software to allow high-speed videography of rat whisker motion to trigger multi-electrode cortical stimuli using their custom stimulation circuits and the Plexon Multichannel Acquisition Processor (Venkatraman et al., 2009). There are several many-channel CMOS IC (complementary metal oxide substrate integrated circuit) systems being developed for use on cultures or brain slices in vitro (Hutzler et al., 2006; Hafizovic et al., 2007; Hottowy et al., 2008; Berdondini et al., 2009), some with integrated stimulation capabilities. Hierlemann and co-workers at ETH Zurich have built an impressive CMOS IC system, expressly designed with closed-loop experiments in mind, such as using living networks as part of a liquid-state machine (Hafizovic et al., 2007). With 128 bidirectional electrodes, on-chip digitization and fast field-programmable gate array (FPGA)-based event detection, this elegant system points the way for future commercial closed-loop systems. However, custom fabrication of mixed-signal (analog and digital) silicon chips is prohibitively difficult and expensive, and beyond the capabilities of most biomedical researchers. Renaud and co-workers are developing an in vitro closed-loop system with electronics comprised of discrete components without custom ICs, and real-time software capable of very fast (sub-millisecond) stimulation feedback. Although the hardware design details and the software code have not been published to date, this promises to be a very flexible, modular system (Bontorin et al., 2007, 2009). We present a simpler and less expensive open-source hardware and software solution for labs wishing to pursue closed-loop electrophysiology using extracellular MEAs, either in vitro or in vivo.