The article discusses the role of amoebae as a "training ground" for the evolution, selection, and adaptation of microbial pathogens. Amoebae, which are ancient ancestors of macrophages, serve as a genetic "melting pot" for horizontal gene transfer between various organisms, including microbes, endosymbionts, and giant viruses. This environment has facilitated the evolution of microbes to evade degradation by amoebae and to survive in mammalian hosts. The article highlights specific examples of microbes that have evolved to evade amoebae, such as *Legionella*, *Chlamydia*, *Coxiella*, *Rickettsia*, *Francisella*, *Mycobacteria*, *Salmonella*, *Bartonella*, *Rhodococcus*, *Pseudomonas*, *Vibrio*, *Helicobacter*, and *Campylobacter*. It also discusses the fungi *Cryptococcus* and *Aspergillus*, as well as amoeba mimiviruses/giant viruses. The co-evolution with amoebae has enhanced the pathogenic potential of microbes, contributing to their ability to infect mammalian cells and cause life-threatening infections. The article emphasizes the importance of further genomic, biochemical, and cellular studies of unicellular eukaryotes to understand the complex interactions between amoebae and microbes.The article discusses the role of amoebae as a "training ground" for the evolution, selection, and adaptation of microbial pathogens. Amoebae, which are ancient ancestors of macrophages, serve as a genetic "melting pot" for horizontal gene transfer between various organisms, including microbes, endosymbionts, and giant viruses. This environment has facilitated the evolution of microbes to evade degradation by amoebae and to survive in mammalian hosts. The article highlights specific examples of microbes that have evolved to evade amoebae, such as *Legionella*, *Chlamydia*, *Coxiella*, *Rickettsia*, *Francisella*, *Mycobacteria*, *Salmonella*, *Bartonella*, *Rhodococcus*, *Pseudomonas*, *Vibrio*, *Helicobacter*, and *Campylobacter*. It also discusses the fungi *Cryptococcus* and *Aspergillus*, as well as amoeba mimiviruses/giant viruses. The co-evolution with amoebae has enhanced the pathogenic potential of microbes, contributing to their ability to infect mammalian cells and cause life-threatening infections. The article emphasizes the importance of further genomic, biochemical, and cellular studies of unicellular eukaryotes to understand the complex interactions between amoebae and microbes.