Malaria is among the most devastating and widespread tropical parasitic diseases in which most prevalent in developing countries. Antimalarial drug resistance is the ability of a parasite strain to survive and/or to multiply despite the administration and absorption of medicine given in doses equal to or higher than those usually recommended. Among the factors which facilitate the emergence of resistance to existing antimalarial drugs: the parasite mutation rate, the overall parasite load, the strength of drug selected, the treatment compliance, poor adherence to malaria treatment guideline, improper dosing, poor pharmacokinetic properties, fake drugs lead to inadequate drug exposure on parasites, and poor-quality antimalarial may aid and abet resistance. Malaria vaccines can be categorized into three categories: pre-erythrocytic, blood-stage, and transmission-blocking vaccines. Molecular markers of antimalarial drug resistance are used to screen for the emergence of resistance and assess its spread. It provides information about the parasite genetics associated with resistance, either single nucleotide polymorphisms or gene copy number variations which are associated with decreased susceptibility of parasites to antimalarial drugs. Glucose transporter PfHT1, kinases (Plasmodium kinome), food vacuole, apicoplast, cysteine proteases, and aminopeptidases are the novel targets for the development of new antimalarial drugs. Therefore, this review summarizes the antimalarial drug resistance and novel targets of antimalarial drugs.