BACKGROUND Drug discovery efforts across the globe are chasing new drug targets and novel mechanisms of action. To support the identification of novel mechanisms of action, phenotype-based drug screening has significantly increased over the last decade. Along with the rise in phenotypic screening, methods and technologies that can help to identify drug targets of phenotypically screened 'hits' have also evolved significantly. METHODS This article provides an overview of successful examples, limitations and advances in small-molecule target identification methodologies. Primarily, the methods are described, where small-molecules without derivatization are used as test-molecules for identifying their direct binding protein partners, the targets, in detail. A brief discussion of other affinity chromatography coupled mass-spectrometry based target identification methods are also presented for comparative appreciation of label-free methods. CONCLUSIONS Label-free methods do not require (a) extensive structure activity analysis of phenotypically screened 'hits' and (b) preparation of tool compounds or target capturing probes for target identification. These methods are significantly shortening the time required for the identification and the downstream validation of targets and hence are gaining popularity as the method of choice for target identification.