A key challenge in the area of determining how the microbiome communicates with the host's karyome is deciding which microbial functions should be studied. Ideally we would wish to look at functions which are not only important to the microbial host, but which also play roles in host physiology. Selecting the key microbial functions is essential to developing robust strategies to either promote or demote them, with the aim to enhancing host health. This commentary argues that the bottom-up approach is not providing the necessary gene-set from which we can start to develop a robust core microbiome and in fact we should adopt a top-down strategy in order to indentify the functions that are important and need further study.