Photoacoustic (PA) imaging is an attractive technology for imaging biological tissues because it can capture both functional and structural information with satisfactory spatial resolution. Current commercially available PA imaging systems are limited by their bulky size or inflexible user interface. We present a new handheld real-time ultrasound/photoacoustic imaging system (HARP) consisting of a detachable, high-numerical-aperture (NA) fiber bundle-based illumination system integrated with an array-based ultrasound (US) transducer and a data acquisition platform. In this system, different PA probes can be used for different imaging applications by switching the transducers and the corresponding jackets to combine the fiber pads and transducer into a single probe. The intuitive user interface is a completely programmable MATLAB-based platform. In vitro phantom experiments were conducted to test the imaging performance of the developed PA system. Furthermore, we demonstrated (1) in vivo brain vasculature imaging, (2) in vivo imaging of real-time stimulus-evoked cortical hemodynamic changes during forepaw electrical stimulation, and (3) in vivo imaging of real-time cerebral pharmacokinetics in rats using the developed PA system. The overall purpose of this design concept for a customizable US/PA imaging system is to help overcome the diverse challenges faced by medical researchers performing both preclinical and clinical PA studies.