In recent years, a series of new viruses were isolated through co-culture with amoebae. These viruses, generally named as “giant viruses” with large virus particles as well as huge genomes, were found to be widely spread over the world. The fact that they encode genes involved in protein synthesis triggered discussion on the issues such as the viral nature and origin. Giant viruses also have the potential to be pathogenic to humans. Here, we reviewed the recent progress on serological, molecular biological, metagenomic detection, and virus isolation of two giant viruses, Mimivirus and Marseillevirus, in human samples, as well as their infection and pathogenesis in mammalian cell lines and animal models.