To overcome the intensive light scattering in the biological tissue, diffuse optical tomography (DOT) in the near infrared range for breast lesion detection usually is combined with other imaging modalities such as ultrasound, X-ray, and MRI, to provide guidance. However, the guided imaging modalities may depend on different contrast mechanics compared to the optical contrast in the DOT. As a result, they can’t provide reliable guidance for diffuse optical tomography because some lesions may not be detectable by a non-optical modality but yet have high optical contrast. An imaging modality which can provide the guidance from optical contrast is desirable for DOT. In this paper, we present a system that combines diffuse optical tomography and photoacoustic tomography (PAT), to detect and characterize the deeply-seated targets embedded in a turbid medium. Photoacoustic tomography utilizes a short-pulsed laser beam to penetrate into tissue diffusively. Upon absorption of the light by the target, photoacoustic waves are generated and used to reconstruct, at ultrasound resolution, the optical absorption distribution that reveals optical contrast. The combined system used in the experiment combines a 64-channel photoacoustic system with a frequency-domain diffused optical system. To further improve the contrast, the exogenous contrast agent, indocyanine green (ICG) is used. Our experiment results show that the combined system can detect a tumormimicking phantom up to 2.5 cm in depth and 10 μM in concentration. Mice experiments also confirmed that the combined system can detect the tumor region and monitor the ICG uptake and washout in the tumor region. This method can potentially improve the accuracy to detect the small breast lesions or any lesions which are sensitive to the reference change, such as the lesions located on the chest wall.