Malaria is an important parasitic disease that, despite great efforts to bring it under control, continues to represent a global public health problem. In an era of globalization where travel to exotic places is no longer unknown, places where malaria is endemic are closer to the rest of the population than ever. According to estimates by the World Health Organization (WHO), 241 million people were infected in these areas in 2020. Most cases of malaria are caused by Plasmodium falciparum. It is also responsible for more severe clinical symptoms and thus a higher number of deaths. Although malaria is a curable disease, people still die from it in endemic areas of the world. An estimated 627,000 people died in 2020 alone. Today, numerous treatment protocols for P. falciparum infection have been developed based on epidemiological and parasitological data relevant to a particular part of the world. From the introduction of the first antimalarials in the 20th century until the development of the ones we use today, P. falciparum has developed resistance to many of them. This meant that the guidelines for the treatment of falciparum-malaria had to keep pace with the development of resistance. The modern progress of science and methods of research of this resistance allows us to understand, at least to some extent, why and how resistance occurred. However, we still do not have concrete and clear answers to some questions and we are still left with hypotheses. The fight against resistance to antimalarials is of great importance for the continuation of the successful treatment of this disease, so the aim of this paper is to present the issue in more detail.