The variations in clinical and biological background of lymphoid malignancies trigger researchers to try to find out novel therapeutic targets. A typical treatment includes multiagent chemotherapy and/or targeted therapy in the light of driver mutations. Next generation sequencing (NGS) plays a pivotal role during the identification of genetic alterations in lymphoid malignancies. A total of 52 patients [30 men (58%) and 22 women (42%)] having normal cytogenetic and FISH results were enrolled in this study. Usage of NGS based targeted sequencing could confirm or support a particularly preferred diagnosis (41/52, 78%) or make a differential diagnosis in cases of interference. Notably, in 11 out of these 52 cases (21%), the initial suspect diagnosis was not supported by the NGS result and thereby had to be reconsidered. In this study, we highlight the importance of targeted NGS panel testing for diagnosis, prognosis and treatment decision in highly selected instances of lymphoid malignancies and lymphoproliferative disorders in which histopathology and more conventional molecular analyses remain inconclusive.