Mice with reduced and imbalanced microbiome have low bone density. Surprisingly, mice with a complete absence of microbiome (born and raised in a germ-free environment) have a higher bone density. The immune system and in particular abnormal maturation of T cells is emerging as a prime candidate responsible for this paradox. The complex interactions between different biological systems including, bone, the immune system and GI, underscore the need to “bone up” and include more comprehensive skeletal and immunological evaluations in toxicology studies as part of a multidisciplinary approach to drug testing.