Klebsiella pneumoniae (K. pneumoniae) is the most prominent type of Klebsiella spp. K. pneumoniae has become a worldwide health threat nowadays due to the emergence of hypervirulence and the extended-spectrum β-lactamases (ESBLs) producing strains that lead to the etiologies of hospital-acquired infections (HAI) and community-acquired infections (CAI). To survive within the host, the bacterium acquires virulence traits and techniques to resist antibiotics and the immune system response, hence it gradually becomes multidrug-resistant (MDR). Consequently, more antibiotics are rendered ineffective and thus inappropriate, causing more deteriorating clinical conditions, leading to a high mortality rate. While the vaccine of K. pneumoniae is still in progress, and since we are long past the beginning of antibiotic use, new concepts came to play to fight the bacterial infection such as the use of bacteriophage to destroy the prokaryotic cell and enhancement of the immune system. This article covers the most common genetic and structural mechanisms of resistance by which K. pneumoniae exhibits its resilience against the defense system and various antibiotics. It also reviews the epidemiology, the leading sites of infections, and possible treatment options for future use.