Malaria causes a high burden of disease worldwide. While there has been a great effort across the globe to decrease incidence through vector control, improved diagnostics, and treatment availability, making major inroads toward eradication remains difficult to achieve. Evolving malarial drug resistance, threats of climate change altering vector habitats, and limited resources in low-income countries in sub-Saharan Africa disproportionately burdened by this disease are a few of the major obstacles. Several factors contribute to the risks for severe disease. Intrinsic factors of the host that can predict more serious infection include extremes of age, undernutrition, immune suppression or immunodeficiency, and a long list of chronic medical conditions. Extrinsic factors that contribute to the complexity of the problem include the causative Plasmodium species, emerging and shifting antimalarial drug resistance, and the quality, availability, and cost of medications and diagnostic tests in highly endemic regions. Timely diagnosis and treatment of malaria is an essential component of reducing overall disease-associated morbidity and mortality.