Co-registering ultrasound (US) and photoacoustic (PA) imaging is a logical extension to conventional ultrasound because both modalities provide complementary information of tumor morphology, tumor vasculature and hypoxia for cancer detection and characterization. In addition, both modalities are capable of providing real-time images for clinical applications. In this paper, a Field Programmable Gate Array (FPGA) and Digital Signal Processor (DSP) module-based real-time US/PA imaging system is presented. The system provides real-time US/PA data acquisition and image display for up to 5 fps* using the currently implemented DSP board. It can be upgraded to 15 fps, which is the maximum pulse repetition rate of the used laser, by implementing an advanced DSP module. Additionally, the photoacoustic RF data for each frame is saved for further off-line processing. The system frontend consists of eight 16-channel modules made of commercial and customized circuits. Each 16-channel module consists of two commercial 8-channel receiving circuitry boards and one FPGA board from Analog Devices. Each receiving board contains an IC† that combines. 8-channel low-noise amplifiers, variable-gain amplifiers, anti-aliasing filters, and ADC's‡ in a single chip with sampling frequency of 40MHz. The FPGA board captures the LVDSξ Double Data Rate (DDR) digital output of the receiving board and performs data conditioning and subbeamforming. A customized 16-channel transmission circuitry is connected to the two receiving boards for US pulseecho (PE) mode data acquisition. A DSP module uses External Memory Interface (EMIF) to interface with the eight 16-channel modules through a customized adaptor board. The DSP transfers either sub-beamformed data (US pulse-echo mode or PAI imaging mode) or raw data from FPGA boards to its DDR-2 memory through the EMIF link, then it performs additional processing, after that, it transfer the data to the PC** for further image processing. The PC code performs image processing including demodulation, beam envelope detection and scan conversion. Additionally, the PC code pre-calculates the delay coefficients used for transmission focusing and receiving dynamic focusing for different types of transducers to speed up the imaging process. To further speed up the imaging process, a multi-threads technique is implemented in order to allow formation of previous image frame data and acquisition of the next one simultaneously. The system is also capable of doing semi-real-time automated SO2 imaging at 10 seconds per frame by changing the wavelength knob of the laser automatically using a stepper motor controlled by the system. Initial in vivo experiments were performed on animal tumors to map out its vasculature and hypoxia level, which were superimposed on co-registered US images. The real-time system allows capturing co-registered US/PA images free of motion artifacts and also provides dynamitic information when contrast agents are used.© (2011) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.