Abstract: The human microbiota comprises 10–100 trillion symbiotic microbial cells constituting over 10,000 microbial species residing in the human body and outnumbering human cells by 10 times. It is now well recognized that human microbiome also viewed as our “other genome” plays a significant role in the development of various human diseases. Changes in composition of the gut microbiome have been investigated for early cancer detection or to identify those individuals at risk of colorectal cancer. In addition, aberrations in the microbiome have been linked to breast, gastric and pancreatic cancers. The identification of microbiome-based biomarkers for disease diagnosis, prognosis, risk profiling, and precision medicine relies on the determination of microbial features associated with health or disease. It is often a daunting task to clearly define what constitutes a healthy microbiome in different human populations, especially because a person’s microbiota can be affected by many factors, including age, lifestyle, diet, smoking, exercise, ethnicity, environmental factors, and other factors. Our lab has been systematically evaluating the role of microbiome in colorectal and uterine cancer to develop a signature that can be detected from matrices other than stool. The challenges and results of these analysis will be discussed in the presentation.