The overall goal of this project is to design and build a state-of-the-art camera system, based on Direct Detection Active Pixel Detector (APD) to provide a vastly improved film substitute for direct digital recording of data for biological Electron Microscopy. Such a system will be immediately applicable and beneficial to cryo-Electron Microscopy (cryo-EM) of macromolecules. The new APD will have an extremely uniform surface and format of 2000x2000 pixels at 10mu/mx10mu/m pitch. As a direct incident electron detector, this device will not require a resolution limiting phosphorescent scintillation screen. The signal to noise ratio for each incident electron will be much higher than the one with a CCD based camera (10/01 vs. 1.1) The spatial resolution is also much better (10 micron, full width at 1/2 maximum and 50 micron at 1/100 vs. 30 and 200 micron) The readout speed of this APD is also much faster than with a CCD (1/10 sec. Vs 1 sec). With this detector, researchers will be able to quickly gather data on hundreds of thousand of images, greatly improving the resolution of 3D structure of the studied macromolecules. While the design and testing of micro-electronics can be costly, the new sensor uses a standard CMOS process and can be reproduced rather inexpensively, As the matter of fact, at the end of this project, we could have enough chips to set up many more detectors. Each pixel of the APD will have a diode that will collect the charges deposited by an incident electron in its passage through a sensitive p-epitaxial layer. It will integrate the collected chards during and exposure period. At the conclusion of the from, the contents of the sensor array are than read out, digitized and stored. All of the integration and read out electronics are implemented within less than 1mu/m of the surface of a 0.25 mu/m CMOS chip, and are transparent to the incident electrons, is 100% due to the fact that the sensitive p-epitaxial layer lies beneath the readout circuitry and is continuous. We intend a phased approach to this research. During the first year, we would like to explore different designs by making and testing many small arrays (256x256 pixels). In the 2nd year, we will select the best design to make and rest medium size chip (526x526 pixels). In the 3rd year we will make and test the large size chip (2Kx2K pixels) and set up the detector.