As malaria control moves towards elimination, there is increasing recognition of the need to address the total human Plasmodium infection prevalence (the “parasite reservoir”), including asymptomatic and sub-patent infections as well as clinical cases. Broadly, there are two approaches to reducing the parasite reservoir that are additional to standard control interventions; mass drug administrations, and targeted approaches. Mass drug administrations (MDA), in which entire populations in malaria-endemic areas are given standard treatments once or in successive rounds, has had mixed success; MDA has mostly been applied to P. falciparum malaria, mostly tested relatively short-term outcomes, and requires substantial resources and intensive community participation strategies to be effective. Alternatively, a range of targeted approaches aim to restrict screening and/or treatment to the population(s) most likely to be infected. Reactive screening and treatment is perhaps the most common targeted approach, but this strategy has also had mixed effectiveness in reducing the parasite reservoir and depends highly on the underlying transmission characteristics. Partly in light of the limitations of approaches such as MDA and reactive household-based screening and treatment, but also to better understand the epidemiology of Plasmodium infection in a malaria elimination era, there have been numerous calls to identify and characterize the parasite reservoir in different settings, to inform the development of appropriate malaria elimination strategies. Through case studies in low-transmission forest malaria settings in Vietnam and Cambodia, we have developed mixed-methods, multi-level research approaches integrating spatial epidemiology, immuno-epidemiology and ethnography for investigating the micro-epidemiology of malaria. Structured micro-epidemiological approaches can lead to improved insights into the causes of fine-scale heterogeneity in malaria transmission, which can be used to guide targeting of vector control, identify pockets of residual transmission and target persistent malaria hotspots in order to achieve malaria elimination.