Leishmaniasis is a group of disease caused by the intracellular protozoan parasite of the genus . Infection by different species of results in various host immune responses, which usually lead to parasite clearance and may also contribute to pathogenesis and, hence, increasing the complexity of the disease. Interestingly, the parasite tends to reside within the unfriendly environment of the macrophages and has evolved various survival strategies to evade or modulate host immune defense. This can be attributed to the array of virulence factors of the vicious parasite, which target important host functioning and machineries. This review encompasses a holistic overview of leishmanial virulence factors, their role in assisting parasite-mediated evasion of host defense weaponries, and modulating epigenetic landscapes of host immune regulatory genes. Furthermore, the review also discusses the diagnostic potential of various leishmanial virulence factors and the advent of immunomodulators as futuristic antileishmanial drug therapy.