Many promising optical molecular imaging modalities, such as bioluminescence tomography (BLT) and fluorescence molecular tomography (FMT) face limitations in detecting deeply embedded optical molecular probes. Based on a biopsy-like optical signal acquisition technique, compressive-sensing-based computational optical biopsy (CSCOB) alleviates the detection depth limitation. CSCOB is minimally invasive to the imaged subject and can perform molecular imaging functionalities on large lab animals or even on human subject. These functionalities can help to monitor drug delivery, evaluate therapy, monitoring cancer growth, and detect early state tumor. CSCOB also has great potential applications in tissue engineering and regenerative medicine. The optical detectors can be integrated into the tissue engineered scaffold along with other nutrients and chemical delivering devices. The multi-functional scaffold can then be implanted into a large animal’s body to grow into an organ. The embedded detectors will continuously read optical information without taking the scaffold out. The CSCOB will be able to monitor the tissue and cell growth as the nutrients and growth factors are delivered and can also detect void volume that has experienced no living cell growth in the later stage. Compare to other optical molecular tomographic modalities, CSCOB is more robust and stable. The reconstruction of BLT and FMT often bears multiple solutions and are sensitive to noise; the reconstruction of CSCOB has a unique solution and the noise in the measurement will not be amplified in the reconstructed probe distribution. The CSCOB modality provides a unique and powerful way in minimally invasive imaging and has great potential to provide highly sensitive molecular imaging in clinical settings.