The human microbiome has been increasingly recognized as having potential use for disease prediction. Predicting the risk, progression, and severity of diseases holds promise to transform clinical practice, empower patient decisions, and reduce the burden of various common diseases, as has been demonstrated for cardiovascular disease or breast cancer. Combining multiple modifiable and non-modifiable risk factors, including high-dimensional genomic data, has been traditionally favored, but few studies have incorporated the human microbiome into models for predicting the prospective risk of disease. Here, we review research into the use of the human microbiome for disease prediction with a particular focus on prospective studies as well as the modulation and engineering of the microbiome as a therapeutic strategy.