The coming decade might become the most challenging for CLL treatment - with an enormous potential to cure this disease, but also with relevant obstacles. Novel, non-genotoxic compounds, which specifically target Achilles heels of CLL cells, such as mitochondria, or the B cell receptor, will complement or even replace classical “chemo-immune-based” regimens. Indeed, results from first clinical trials in heavily pretreated patients exceeded all expectations, since treatment with ABT-199, ibrutinib or idelalisib dramatically improved the response rates. However, clinical trials with these novel compounds indicate that patients with high-risk settings, such as loss of p53 still have the worst outcome. Our own pre-clinical data showed CLL cells to be resistant to extrinsic apoptosis, but sensitive towards the intrinsic apoptosis pathway, which is targeted by venetoclax. Moreover we could show for the first time that venetoclax acts synergistically with ibrutinib and idelalisib. However, first data from longer follow-up clinical trials indicate that venetoclax results in so far unknown resistance mechanisms accompanied by a very aggressive course of disease with a high mortality. Our aims will directly test the hypotheses that: 1) resistance mechanisms towards venetoclax are dependent on p53 as a critical upstream regulator of mitochondrial apoptosis, 2) resistance towards venetoclax does not occur solely on the level of DNA mutations.