Three different paradigms among vectorborne diseases will be illustrated by the models Plasmodium, Leishmania and Schistosoma, respectively (Fig. 1). Plasmodium spp. are protozoan parasites (Sporozoa) that reproduce asexually in their host and have an obligatory sexual life cycle in the mosquito host. Infections with Plasmodium falciparum, the most important human malaria parasite, can be very diverse: up to five and sometimes well in excess of ten genotypes can infect a single host in high transmission areas (Konate et al., 1999; Beck et al., 2001; Magesa et al., 2002; Sutherland et al., 2002; Juliano et al., 2010; Auburn et al., 2012). Resistance to all previous first-line treatments is already widespread (Hyde, 2005), and resistance against the only available first-line treatment that has not yet failed globally, the artemisinin derivatives, may be on the rise (Dondorp et al., 2010). The antimalarial resistance problem seems to be largely driven by the transmission of resistant parasites, opposed to frequent emergence of new mutants in various regions (Wootton et al., 2002; Nair et al., 2003; Hastings, 2004; Mita et al., 2011). Leishmania belong to another group of Protozoa (Kinetoplastida). They have a predominantly asexual reproduction mode in both vertebrate and invertebrate hosts, but may nevertheless undergo recombination between individuals, related (endogamy) or not (Rougeron et al., 2010). Albeit within-host multiclonality is poorly studied, it is likely to be very low, considering the low infection rates among sand fly vectors (Bhattarai et al., 2009) and the strong immunity after recovery from infection (Modabber, 2010). Transmission dynamics of Leishmania are rather slow; hence, frequent emergence of resistance likely plays a major role, as confirmed by whole genome sequencing studies (Downing et al., 2011). In addition, transmission may be predominantly driven by individuals not eligible for treatment, such as asymptomatically infected humans in case of anthroponotic leishmaniasis (Stauch et al., 2012) or animals in case of zoonotic forms. In this context, it is striking how drug resistance may persist, and fitness appears to be an essential feature to consider. Schistosoma are metazoan parasites (Trematoda) showing a complex life cycle with an obligatory alternation of sexual reproduction within the final human host and asexual reproduction within the intermediate snail host. A major conceptual difference with protozoa is the absence of replicative stages in the human host, with adults living in their hosts' blood for up to 10 years and where the female produces about 200–1000 eggs per day that need to be excreted to the environment to complete the life cycle (Gryseels et al., 2006). A single host can be infected by many different schistosome genotypes, resulting in large populations showing high genetic variation (Agola et al., 2006, 2009; Rudge et al., 2008; Thiele et al., 2008; Gower et al., 2012). Infection loads are, however, aggregated (Anderson & May, 1991) with many people having low-intensity infections that are asymptomatic and not obvious enough to warrant treatment. Despite several alarming reports of Schistosoma mansoni resistance foci against the two most commonly used drugs, praziquantel (PZQ) and oxamniquine (OXA), resistance did not spread as there is no indication that it has become a serious public health problem (Cioli et al., 1993; Doenhoff et al., 2002; Doenhoff & Pica-Mattoccia, 2006; Wang et al., 2012). Nevertheless, OXA resistance showed stronger characteristics than PZQ resistance: OXA-resistant S. mansoni resisted to very high doses of the drug (Pica-Mattoccia et al., 1993), while S. mansoni isolates frequently exposed to PZQ differed maximum threefold in their tolerance to the drug compared with susceptible strains (Cioli et al., 2004).