It has become essential in the drug development to quickly separate, quantify and identify all possible impurities within a sample.Apart from fulfilling the needs of fast purity assessment, another major challenge is to study the specificity of method to ensure there is no peaks co-eluting with the compound of interest.The conventional way to perform peak purity assessment or specificity study is to start with using two orthogonal methods, then compare their results.However this can be very time consuming.Recently multidimensional (2D-LC) separation has been investigated for improved productivity and data quality.Several applicable 2D-LC designs have been recently proposed [1,2].The purpose of using 2D-LC operated in either "heart-cut" or "comprehensive" mode is to provide optimal efficiency and selectivity for separation of the component of interest, and also to prove that no other compounds co-elute with the compound of interest.Our approach is based on a simple fully-automated design aming to implement a true orthorgonal separation for both achiral and chiral analysis.Applications using 2D-LC-MS for specificity studies, impurity profiling and chiral separations will be presented.