Malaria is a vector-borne infection common in tropical and subtropical countries. The immunological reactions warranted by the malaria Plasmodium falciparum parasite occur with multiple features, as seen in the human host and in the Anopheles mosquito. Numerous methods using phytomedicines and molecular strategies exist for disruption of Plasmodium transmission. Herein, the molecular and cellular basics occurring in the vector and host immune response are explicitly discussed with a view towards effective drug targeting. A key area of interest to target for vaccine development is the CD4 + T helper cells production of proinflammatory cytokines that activate macrophages, thus promoting the activation of specific B cells as seen in the erythrocytic stage where the action of CD8 + T cells is thought to be insignificant. Similarly, the γδT and NK cells with IFN-γ, perforin and granzyme produced being implicated in destroying RBCs infected with P. falciparum. Moreover, some genetic markers such as the Dantu red blood cell variant, ABO blood group system, hemoglobinopathy, glucose 6 phosphate dehydrogenase deficiency, etc., associated with natural resistance to malaria parasites are also espoused. Through the course of human development, immune response to various toxicants, shown some elasticity towards microbial exposures, driving epigenetic modifications allowing innate immune cell programming. Malaria co-infection remains an issue, evidence suggests malaria and HIV infections, for instance, undergo bidirectional and synergistic interaction. Moving forward, some important biological receptors such as ferriprotoporphyrin, the involvement of anti Plasmodium IgG, SMI peptide and cyclotide antimicrobial peptide, regulate Plasmodium parasite immune response in the mosquito and possibly human host and the interaction of complement factors may bring about the immunological reaction to infection with Plasmodium. The incorporation of different clinical, genetic markers and epigenetic factors may help establish utility that may bring about a novel control mechanism involving molecular and epigenetic properties for malaria disease.