Microbiome science has contributed greatly to our understanding of microbial life and provided crucial insights on the pivotal roles and capabilities of microbial communities on our planet. However, we still lack a comprehensive understanding of how these communities are assembled, maintained, and function as a system. In particular, the underlying mechanism of microbe-microbe and microbe-host interactions remain poorly understood. We therefore developed new approaches to unravel interactions in complex microbiomes by determining the niches these microbes occupy. Synthetic microbial communities (SynComs) enabled us to benchmark these methods and to compare data derived from SynComs to natural communities. Integrating next generation modeling with experimental approaches provided mechanistic insights into these interactions. We can now selectively alter complex microbiomes, predict outcomes, and design successful interventions. The approach has been applied to a broad range of microbiomes, in vitro and in vivo, and thus is a versatile tool for microbiome manipulation across diverse ecosystems - from agricultural settings to human health.