Modern treatment approaches such as chemoimmunotherapy (e.g., fludarabine/cyclophosphamide/rituximab or FCR) are highly effective in the majority of chronic lymphocytic leukemia (CLL) patients. However, there remains a small but challenging subgroup of patients who show ultra high-risk genetics (17p deletion, TP53 mutation) and/or poor response to chemoimmunotherapy. The median life expectancy of these patients is below 2 to 3 years with standard regimens. Accordingly, CLL with the 17p deletion (and likely also with sole TP53 mutation) should be treated with alternative strategies. While p53 defects appear to play a central role in our understanding of this ultra high-risk group, at least half of the cases will not be predictable based on existing prognostic models. Current treatment approaches for patients with p53 defects or poor response to chemoimmunotherapy should rely on agents acting independently of p53, such as alemtuzumab, lenalidomide, flavopiridol, and a growing number of novel compounds (or combinations thereof) currently available in clinical trials. Poor survival times of patients with ultra high-risk CLL suggest that eligible patients should be offered consolidation with reduced-intensity allogeneic stem-cell transplantation or experimental approaches in clinical trials.