This thesis provides an analysis of the Monkeypox virus (MPXV), examining the genomic features and evolutionary mechanisms driving its global re-emergence. The research characterizes MPXV's genetic architecture, documents the divergence between Clade I and Clade II viruses, and identifies the specific adaptive mutations that enabled the unprecedented international spread of Clade IIb. Through comparative analysis with other orthopoxviruses, the study reveals MPXV's unique position at the intersection of animal reservoirs and human transmission networks. The findings highlight critical gaps in current surveillance systems and demonstrate how genomic epidemiology can illuminate transmission pathways and viral adaptation, providing essential insights for developing targeted interventions against this ongoing public health threat.