Currently, many drugs used to treat malaria are alkaloids or their synthetic derivatives. The primary natural sources of these compounds are plants and certain marine species. Numerous in vitro and in vivo studies have demonstrated the strong activity of alkaloids against various Plasmodium spp. strains, although cytotoxic effects have also been observed. Several chemical synthesis schemes have been developed to improve their potency, effectiveness, physicochemical properties, and reduce toxicity. Current trends focus on conducting molecular dynamics studies related to different malaria targets, as well as investigating the interaction of alkaloids and their derivatives with different parasite targets. However, significant challenges remain in developing antimalarial drugs that are effective against resistant strains and have reduced toxicity. This chapter discusses some of these challenges and highlights the most notable findings published to date.