During the last decade, viral studies have investigated truly large viruses for the first time in the history of biology. Those giants of viruses include Acanthamoeba polyphaga mimivirus with a 1.18 Mbp dsDNA genome encoding more than 1,000 genes and a recently isolated “Pandoravirus salinus” (currently unclassified) with a 2.77 Mbp dsDNA genome encoding 2,556 genes. They are part of the classically defined nucleocytoplasmic large DNA virus group, but they generate large virions that are comparable in size with bacterial cells. The discovery of giant viruses has triggered the reexamination of classical virus perceptions, such as “viruses are non-organisms,” and has elicited provocative proposals related to the nature of viruses. In this chapter, we review the fascinating biology of giant viruses uncovered by genomics during recent years. Then we introduce several proposed hypotheses related to the origin and nature of those giant viruses, including the fourth domain hypothesis, the viral eukaryogenesis hypothesis, and the virocell concept. Giant virus research is still in its infancy, but is likely to reveal increasingly fascinating biological phenomena and is expected to engender a novel evolutionary perspective unifying the viral and cellular worlds.