Transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL) is known as Richter syndrome (RS). In the entire CLL population, the cumulative prevalence of RS development steadily increases at a rate of 1% per year. Considering conventional predictors of CLL, patient subgroups at high risk of developing RS are characterized by the expression of CD38, absence of del13q14, and a lymph node size >3 cm. Novel risk factors for predicting RS development at CLL diagnosis have been recently identified and include: the host genotype of the CD38 locus and of other genes; telomere length of CLL cells; stereotyped B-cell receptor; and usage of specific immunoglobulin variable genes (IGHV4-39). Importantly, although some risk factors predict both CLL progression and transformation to RS, others (CD38 genotype, absence of del13q14, IGHV4-39 usage, stereotyped B-cell receptor) appear to specifically predict RS. The definition of RS encompasses at least two different conditions: DLBCLs that are clonally related to the pre-existing CLL (accounting for most cases), or DLBCL unrelated to the CLL clone. The transition from CLL to clonally related RS is accompanied by the acquisition of novel genetic alterations that may account for the chemorefractoriness of RS. Genome-wide studies that are currently ongoing are important for identifying novel molecular lesions implicated in RS that might represent a suitable target for future therapeutic strategies.