Predicting the total number of microbial cells on Earth and exploring the full diversity of life are fundamental research concepts that have undergone paradigm shifts in the genomic era. In this issue, Lloyd and colleagues (K. G. Lloyd, A. D. Steen, J. L. Ladau, J. Yin, and L. Crosby, mSystems 3:e00055-18, https://doi.org/10.1128/mSystems.00055-18, 2018) present results that combine these two concepts by estimating the total diversity of all cells from Earth's environments. Leveraging publicly available amplicon, metagenomic, and metatranscriptomic datasets, they determined that nearly all environments are dominated by uncultured lineages, with the exception of humans and human-associated habitats. They define a new concept: phylogenetically diverse noncultured cells (PDNC). Unlike viable but nonculturable cells (VBNC), PDNC are microorganisms for which traditional isolation techniques may never succeed. Lloyd et al. estimate that the majority of microorganisms in Earth's ecosystems may be PDNC and conclude that culture-independent methods combined with innovative culturing techniques may be required to understand the ecology and physiology of these abundant and divergent microorganisms.