Klebsiella pneumoniae (K. pneumoniae) is a Gram-negative commensal bacterium and opportunistic pathogen. In healthy individuals, the innate immune system is adept at protecting against K. pneumoniae infection. Notably, the serum complement system and phagocytic leukocytes (e.g., neutrophils) are highly effective at eliminating K. pneumoniae and thereby preventing severe disease. On the other hand, the microbe is a major cause of healthcare-associated infections, especially in individuals with underlying susceptibility factors, such as pre-existing severe illness or immune suppression. The burden of K. pneumoniae infections in hospitals is compounded by antibiotic resistance. Treatment of these infections is often difficult largely because the microbes are usually resistant to multiple antibiotics (multidrug resistant MDR). There are a limited number of treatment options for these infections and new therapies, and preventative measures are needed. Here, we review host defense against K. pneumoniae and discuss recent therapeutic measures and vaccine approaches directed to treat and prevent severe disease caused by MDR K. pneumoniae.