Combining voltage and Ca2+ imaging allows correlation of electrical and chemical activity at sub-cellular level. We developed and commercialised an imaging system designed to obtain simultaneous voltage and Ca2+ measurements with high signal-to-noise ratio from sites as small as a few microns. Using the combination of the commercial voltage sensitive dye JPW1114 and of a UV excitable Ca2+ indicator, these measurements can be obtained with negligible optical cross-talk between the two signals and negligible photo-damage of the preparation. More recently, we started using the recently developed voltage sensitive dye Di-2-ANBDQ(F)PTEA emitting in the IR. This dye can be combined with blue excitable calcium indicators (Calcium Green, Oregon Green or Fluo) permitting the use of simultaneous UV illumination for uncaging. In this presentation I will start showing published results using commercial indicators demonstrating the capability to obtain single-trial resolution from sites as small as 2 microns. I will then present some novel results using a new fast CCD camera permitting acquisitions of both voltage and Ca2+ wavelengths at high speed (up to 20 kHz). This high speed is particularly relevant when using Ca2+ indicators with equilibrium constant > 10 µM which are able to follow Ca2+ signals in less than a millisecond. Thus, using these indicators, it is possible to follow the fast rise time of Ca2+ currents associated with an action potentials and correlate them with local changes of membrane potential. The problem of calibrating optical signals will be also addressed in detail. In summary, the experimental approach presented here opens the gate to many novel physiological investigations requiring simultaneous measurement of voltage and Ca2+ signals.