The introduction of genotypic tools to analyze Mycobacterium tuberculosis isolates has transformed our knowledge of the transmission dynamics of this pathogen. We discuss the development of the laboratory methods that have been applied in recent years to study the epidemiology of M. tuberculosis. This review integrates two approaches: on the one hand, it considers how genotyping techniques have evolved over the years; and on the other, it looks at how the way we think these techniques should be applied has changed. We begin by examining the application of fingerprinting tools to suspected outbreaks only, before moving on to universal genotyping schemes, and finally we describe the latest real-time strategies used in molecular epidemiology. We also analyze refined approaches to obtaining epidemiological data from patients and to increasing the discriminatory power of genotyping by techniques based on genomic characterization. Finally, we review the development of integrative solutions to reconcile the speed of PCR-based methods with the high discriminatory power of whole-genome sequencing in easily implemented formats adapted to low-resource settings. Our analysis of future considerations highlights the need to bring together the three key elements of high-quality surveillance of transmission in tuberculosis, namely, speed, precision, and ease of implementation.