Diseases caused by intracellular pathogens represent a major public health problem worldwide, including the Middle East. The cellular plasma membrane acts as a portal for the entry of intracellular pathogens. An essential step for an intracellular pathogen to gain entry into a host cell therefore is to be able to cross the cell membrane. In this talk, I will highlight the role of host membrane cholesterol in regulating the entry of intracellular pathogens such as Leishmania and Mycobacterium. Our results show that pathogen entry is inhibited either upon depletion (or complexation) of membrane cholesterol. We propose a general mechanism, based on cholesterol-induced conformational changes, involving cholesterol binding sites in host cell surface receptors that are implicated in pathogen entry. A therapeutic strategy targeting modulation of membrane cholesterol has the advantage of avoiding the commonly encountered problem of drug resistance in tackling infection by intracellular pathogens. Interestingly, our results show that an optimum level of host membrane cholesterol is necessary for efficient infection by pathogens. We envision that insights into the role of host membrane cholesterol in pathogen entry would be instrumental in the development of novel therapeutic strategies to effectively tackle intracellular pathogenesis.