Amoebae-resistant microorganisms exhibit a specific lifestyle. Unlike allopatric specialized intracellular pathogens, they have not specialized because they infect the amoebae via amoebal attack and present a sympatric lifestyle with species from different phyla. In this review, we compare the genomes from bacteria (Legionella pneumophila, Legionella drancourtii, Candidatus'Protochlamydia amoebophila,' Rickettsia bellii, Candidatus'Amoebophilus asiaticus') and a virus (mimivirus) that multiply naturally in amoebae. The objective is to highlight the genomic traits characterizing these microorganisms and their niche by comparison with other specialized pathogens. The genome of intra-amoebal microorganisms is significantly larger than that of their relatives, contradicting the genome reduction theory mostly accepted for intracellular pathogens. This is probably due to the fact that they are not specialized and therefore maintain their genome size. Moreover, the presence of many horizontally transferred genes and mobilomes in their genomes suggests that these microorganisms acquired genetic material from their neighbors and amoebal host, thus increasing their genome size. Important features involved in gene transfer and pathogenicity were thus acquired. These characteristics suggest that amoebae constitute a gene melting pot, allowing diverse microorganisms to evolve by the same pathway characterized by gene acquisition, and then either adapt to the intra-amoebal lifestyle or create new pathogens.