Leptospirosis is a globally important zoonotic disease and an important public health problem in developing countries. Early diagnosis is essential because antibiotic treatment is most effective when initiated early in the course of the disease. Culture and the microscopic agglutination test are gold standard methods for leptospirosis diagnosis; however, they are not useful for early diagnosis. Current whole cell-based rapid serological tests have low sensitivity for early phase leptospirosis and may have low specificity in highly endemic areas. PCR is demonstrably useful for early diagnosis, but it is unavailable in most developing countries. Thus, diagnostic methods that not only have higher sensitivity and accuracy for early phase leptospirosis but are also widely applicable in developing countries remain to be developed. The availability of genome sequences and genetic tools of Leptospira spp. will accelerate our understanding of Leptospira pathogenesis and provide insights into the development of more efficient and accurate diagnostic tests for acute-phase leptospirosis.