Animal models have the potential to probe disease mechanisms and test novel treatments prior to human use, but any model is only as good as the tools available to analyze its output. Non-invasive imaging of animal models enables researchers to visualize and quantify disease processes, evaluate treatments, and refine experimental designs. Optical coherence tomography (OCT), with depth penetration of up to 2 mm and axial and lateral resolution in the range of 10 μm for research applications, gives researchers new tools for their preclinical platforms. Here we present how researchers are using OCT for skin, brain, and cardiovascular research, showing how OCT can enhance each of these fields. Murine models of skin conditions can be visualized non-invasively with greater penetration than dermoscopy. Murine brain imaging by OCT, typically achieved by inserting a cranial optical window prior to experimentation, gives greater penetration and more structural information than confocal microscopy. Non-invasive cardiovascular studies performed by OCT endoscopy enable improved tissue characterization due to OCT’s depth penetration. In a complementary fashion, small animals can drive research into enhanced software and hardware improvements for OCT imaging. In this chapter, we hope to provide preclinical researchers with a comprehensive summary of how OCT, through its powerful visualization strategies, can be leveraged to enhance our understanding of disease.