Over the last two decades, the role of the commensal microbiota in human health has received enormous research interest. There has been significant progress in detailing the composition and activities of the microbiota at various anatomic sites and correlating distortions in microbiota with various health and disease endpoints. However, to date there appears to be a sparsity of evidence sufficient to support a causal contribution of microbiota to human health and disease. Establishing causality, beyond simple correlations, is crucial for the future development of microbiota targeting prevention regimen. Using examples from our microbiota research I will elaborate on these concepts and discuss potential approaches to advance the field.