Lymphomas are a group of hematological malignancies derived from lymphocytes. Lymphomas are clinically and biologically heterogeneous and have overlapping diagnostic features. With the advance of new technologies and the application of efficient and feasible detection platforms, an unprecedented number of novel biomarkers have been discovered or are under investigation at the genetic, epigenetic, and protein level as well as the tumor microenvironment. These biomarkers have enabled new clinical and pathological insights into the mechanisms underlying lymphomagenesis and also have facilitated improvements in the diagnostic workup, sub-classification, outcome stratification, and personalized therapy for lymphoma patients. However, integrating these biomarkers into clinical practice effectively and precisely in daily practice is challenging. More in-depth studies are required to further validate these novel biomarkers and to assess other parameters that can affect the reproducibility of these biomarkers such as the selection of detection methods, biological reagents, interpretation of data, and cost efficiency. Despite these challenges, there are many reasons to be optimistic that novel biomarkers will facilitate better algorithms and strategies as we enter a new era of precision medicine to better refine diagnosis, prognostication, and rational treatment design for patients with lymphomas.