The last two decades have seen a major increase in our understanding of the role of the microbiome in health and disease. We now realise that these fellow travellers are really important regulators of various systems in the body across the lifespan. In this Special Issue, we bring together a collection of articles from leading authors who summarise the current state of the art of host-microbe interactions. While we celebrate the breakthroughs in microbiome science, we also acknowledge the challenges-variability in microbiota composition, the complexities of host-microbe interactions and the need for standardised methodologies. As research progresses, harnessing the power of the microbiome may pave the way for novel diagnostic and therapeutic strategies, reaffirming the notion that we are never alone-our microbial fellow travellers accompany us through life, for better or worse.