This study examines the challenge of comparability of different sequencing platforms and discusses the historical background and characteristics of the most commonly used sequencing instruments. Next-generation sequencing is a technology that could potentially replace many traditional microbiological workflows, providing clinicians and public health specialists with more actionable information than hitherto achievable. This paper hypothesises that the future directions of the technology will move it towards performing sequencing directly from the clinical specimen, leading to another fundamental transformation of clinical diagnostics and public health surveillance.