Opportunistic pathogenic bacteria continuously live in humans and obligately pathogenic bacteria associate with humans only in the case of diseases. A mystery is whether pathogens can live outside the hosts. We showed here that most human pathogens have lost biosynthetic pathways for amino acids. This condition suggests that most microbial pathogens are obligately host-dependent and they cannot multiply outside their hosts. Further analysis of the genome sizes revealed that the genomes of host-dependent bacteria are smaller than those of free living bacteria, suggesting that reductive evolution of genomes occurs broadly in bacterial pathogens and non-pathogens closely associated with human and animal hosts. The extent of genome reduction appears to depend on the environment in which they reside. The richer the nutrients are in the environment the smaller the genome is in the bacteria.