Most of the variance in the human microbiome remains unexplained. Although an extensive list of individual lifestyles shaping the microbiome has been identified, important gaps in knowledge persist. Most human microbiome data are from individuals living in socioeconomically developed countries. This may have skewed the interpretation of microbiome variance and its relationship to health and disease. Moreover, striking under-representation of minority groups in microbiome studies is a missed opportunity to assess context, history and the changing nature of the microbiome in relation to the risk of disease. Therefore, we focus here on areas of recent progress — ageing and ethnicity — both of which contribute to microbiome variance with particular lessons for the promise of microbiome-based diagnostics and therapeutics.