- Malaria is a resilient disease characterized by complex life histories of the pathogen and the vector, and still is a major threat to global development. We introduce a population-genetic framework for the evolutionary processes, exemplified but not restricted to anti-malarial drug resistance, which accurately incorporates malaria transmission. In particular, the dynamics of resistance-conferring mutations and their impact on neutral genetic variation (genetic hitchhiking) are modeled. It is shown that the processes of selection and recombination cannot be separated as in standard population-genetic models. Indeed the interplay of selection and recombination is mediated by multiplicity of infection (MOI), i.e., the number of (super-) infections within the course of the disease. Importantly, the extent of genetic hitchhiking (or, equivalently, linkage disequilibria) around resistance-conferring alleles crucially depends on MOI. The advantage of the framework is that vector dynamics and intra-host dynamics do not need to be modeled explicitly. Vector dynamics enter the model via MOI, while intra-host dynamics are subsumed by fitness parameters. Complementary models can be incorporated to elucidate the mechanisms underlying these parameters. In particular, it is shown how MOI and selection parameters can be estimated from molecular data. Furthermore, we discuss how the parasite’s life history inside the host translates to evolutionary fitness. These considerations explain why anti-malarial drug-resistance evolution is faster in P. falciparum than in P. vivax.