After two decades of evolution, Atomic Force Microscopy (AFM) has established its strong existence in the material science research field with its nanoscale resolution. Of the systems out in the market, the innovative XE-AFMs have overcome the non-linearity and non-orthogonality problems associated with traditional piezoelectric tube based AFMs. Active in both research and industrial applications including hard-disk, microchip fabrication, and quality control, the XE series has been widely adopted in the nanometrology field. The most recent addition to the XE family, the XE-Bio, has integrated the high resolution of AFM imaging and non-invasiveness capabilities Scanning Ion Conductance Microscopy with the versatility of advanced optical microscopy techniques such as scanning confocal microscopy, FRET and TIRF. Therefore, the XE-Bio is able to correlate the highest possible spatial resolution with dynamic functionality studies on live biological samples.