The emergence and spread of drug-resistant malaria represents a considerable challenge in controlling malaria. Artemisinin compounds are highly potent, rapidly eliminated drugs and clear parasitemia most rapidly when compared to any other antimalarial. The World Health Organization (WHO) recommends use of artemisinin combination therapy (ACT) against Plasmodium falciparum (PF) malaria to ensure high cure rates and prevent development of resistance against artemisinin compounds. However, resistance to artemisinins has emerged in Cambodia and is spreading to the Greater Mekong Subregion (GMS) and through India to Africa. Signs of resistance to the ACT - artesunate sulfadoxine pyrimethamine in PF has been observed in north-eastern states of India. We report four cases of complicated malaria in Andhra Pradesh-Orissa border over a five month period, with apparent treatment failure with artemisinin drugs, and all showing parasitological clearance after administration of quinine and adjuvant clindamycin therapy. However, one case died due to complications of malaria. We highlight the need for increased monitoring and surveillance to identify artemisinin combination therapy resistance in other parts of India apart from North-eastern states. We also explore the likely factors contributing to this rapid emergence and spread of artemisinin resistance across the world.