Grassi's allegory of the fragile feet of clay of the malaria giant applies particularly to Plasmodium falciparum marginal populations in temperate climates such as those that spread within the last three thousand years in the Mediterranean area through their close association with non diapausing vectors of the Anopheles maculipennis complex. The winter survival of the vector and the successful completion of the sporogonic cycle depended on the availability of the house environment to the mosquito. The fragility of the parasite's cycle became especially evident with the crucial impact of indoor-sprayed residual insecticides resulting in very rapid malaria eradication. The malaria giant showed to possess much more solid feet in the Tropics where P. falciparum eventually reached an exceptionally stable endemicity in sub-Saharan Africa due to a vectorial system which produces inoculation rates far higher than the minimum necessary to saturate human populations. This very high transmissibility resulting from recent human-dependent speciation processes in Afrotropical Anopheles mosquitoes (namely the emergence in the Neolithic period of specifically anthropophilic taxa in the An. funestus and An. gambiae complexes) had probably a key influence on the origin of the modern P. falciparum from an ancestral, less pathogenic, taxon. It is hypothesised that under the prevalence of multiple inoculation during epidemic flashes, a fast growing, aggressive strain responsible for acute, short-lived infections was selected. This quickly replaced the ancestral taxon and spread all over the world taking advantage of previous Anopheles radiation and of the demographic expansion following the agricultural revolution. Dealing with the African 'roots' of the malaria giant means to face both the exceptional stability of the parasite cycle and the risk of disrupting the human natural response with unsustainable interventions. Most efforts should be concentrated in the support and improvement of the available anti-disease strategies whereas the development of effective anti-infection strategies should be mainly pursued through reasonably diversified research programmes and well monitored pilot interventions within a long-term perspective. The aim is to discover and test new anti-malarial tools which either alone or, more probably, integrated with the available measures, could allow the interruption of transmission. In most Afrotropical hyper- and holoendemic zones, once given full priority to strengthening disease control, P. falciparum eradication appears the only realistic anti-infection objective, unless it is demonstrated that progress can be achieved in these epidemiological zones through sustainable and cost-effective intermediate steps based on the reduction of infection prevalence.