Timely and accurate diagnosis is a critical aspect of malaria surveillance, treatment, and intervention campaigns. Currently, field malaria diagnostics rely almost primarily on light microscopy and rapid diagnostic tests. However, both methods miss a significant proportion of asymptomatic patients and perform poorly in low transmission settings. In this review, we present tools that have been used by U.S. Naval Medical Research Unit (NAMRU) SOUTH and its collaborators during the last 40 years for various aspects of malaria research, including clinical trials, outbreak response, and epidemiologic surveillance in South and Central America. Overall, the current and future toolbox for malaria diagnostics needs to be carefully evaluated and tailored to the malaria transmission dynamics in each focus to maximize its effectiveness and achieve the goal of malaria elimination.