Abstract: A wide array of fast replicating and mutating endogenous viruses with temporal and spatial variability predominate human and zoonotic genomes with and without disease manifestations. However, knowledge about their composition, complexity and dynamics is inadequate. Till date high throughput genomic, transcriptomic and proteomic studies revealed some significant findings on tripartite interaction among virome-microbiome and human behaviors that greatly impact human physiology and homeostasis. Rich repertoires of endogenous viruses provide beneficial attributes to the host, and confer adverse immune modulation and secondary infections. Many of these human inhabiting viruses arise due to cross species transmission from mammals and birds, which leads to lethal epidemics. Comprehension on viral taxonomy, viral proteomic elements and factors responsible for host virome interactions will certainly aid to formulate strategies against future viral outbreaks. The review summarizes some of the key aspects in virome metagenomic studies in correlation with human health and diseases.