We present enhanced truncated-correlation phototothermal coherence tomography (eTC-PCT) for non-invasive three-dimensional imaging of small animals. Tumor detection is reported in a mouse thigh by injecting cancerous cells in the thigh followed by eTC-PCT imaging. Detection of the tumor 3 days after injection may lead to potential for using the eTC-PCT method for cancer treatment studies. eTC-PCT was also applied successfully to non-invasive in-vivo mouse brain structural imaging. A unique spatial-gradient-gate adaptive filter was introduced in a scanned mode along the (x,y) coordinates of camera images from different sub-cranial depths, revealing absorber true spatial extent from diffusive photothermal images and restoring pre-diffusion lateral image resolution beyond the Rayleigh criterion limit in diffusion-wave imaging science. The spatial resolution and contrast enhancement demonstrated in photothermal in-vivo and ex-vivo images of the mouse brain revealed not only vascular structures but also other brain structures, such as the brain hemispheres, cerebellum, and olfactory lobes. Optical imaging provides intrinsic advantages in biological tisssue characterization through the capacity for high image contrast and resolution. However, purely optical methods are hindered by their penetration depth being effectively limited to the optical diffusion length. Recently, two-photon microscopy 1 , three-photon microscopy 2 , and optical coherence tomography 3 were utilized for in-vivo brain imaging with the depth range of ~ 1.6 mm within the cortex layer and resolution of a few micrometers. This, however, was only possible in an invasive mode, after removing the skin and removing/thinning the skull. Although the image resolution of purely optical imaging methods is very high, the invasive nature of these methods limit their application for e.g. drug testing. Recently, photoacoustic tomography (PAT) has been explored for non-invasive cancer tumor imaging 4-7 and brain imaging applications as an alternative to purely optical imaging 8-13. Through exploiting the optical-to-ultrasonic energy conversion, photoacoustic methods combine high optical contrast with the superior penetration depth of ultrasonic waves. However, the reported setups require animal models to be surrounded by a coupling medium, often water, thus limiting the potential use of PAT. They also require the use of single transducer or array scanning which complicates the instrumentation and the image acquisition process. Light absorption and nonradiative energy conversion in the sample leads to the photothermal effect, which gives rise to thermophotonic imaging, an emerging photothermal diagnostic modality. It involves the detection of photothermal waves through emitted thermal infrared (IR) photons (Planck radiation) from tissues, captured by a mid-IR (MIR) camera. Enhanced Truncated-Correlation Photothermal Coherence Tomography (eTC-PCT) 14 is a novel imaging method based on the photothermal effect, which has achieved superior penetration