Multimodality small-animal molecular imaging has become increasingly important as transgenic and knockout mice are produced to model human diseases. With the ever-increasing number and importance of human disease models, particularly in rodents (mice and rats), the ability of high-resolution multimodality molecular imaging instrumentation to contribute unique information is becoming more common and necessary. Multimodality imaging with high spatial resolution and good sensitivity, which combines modalities and records sequentially or simultaneously complementary information, offers many advantages in certain research experiments. This article discusses the current trends and new horizons in preclinical multimodality imaging in-vivo and its role in biomedical research.