Early detection and prevention of colorectal cancer are the primary goals and most impactful strategies for the reduction of mortality from colorectal cancer. Distinguishing high-risk polyps from benign lesions is essential for proper management. This has become largely important with respect to the increase in pathology costs, in addition to the risk of procedural complications. Various technologies and techniques have been developed with the intent of direct visualization and better analysis of the targeted tissue. Optical biopsy has become a potential tool to allow in vivo polyp diagnosis, allowing for proper selection of those polyps that require resection and definitive diagnosis of resected polyps without histology. In this review, we will discuss enhancement technologies in colonoscopy, focusing on the “optical biopsy” methods. High-resolution and high-definition technologies enabled the development of such a myriad of methods. Diagnosis of early neoplastic changes in vivo during endoscopic procedures is currently possible owing to the “optical biopsy” technologies. One should still be careful when considering them as conclusive diagnoses because the criterion standard remains to be the pathology analysis. Despite its promising use, high cost and training are still significant challenges. In addition, further research is required regarding the analysis of cellular and molecular levels and the need for a more precise contrast. Although the indications for the use of these new technologies are still being established, the necessity of lowering costs and improving efficiency will likely counterweigh this new challenge.