The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients’ enrolment in oncology trials shifts towards the implementation of molecular profiling as prescreening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i)longitudinal cohort studies that implement(or not) “nested” downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) “master” protocol trials, iv) “basket” trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials. The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. from paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients ’enrolment in oncology trials shifts towards the implementation of molecular profiling as prescreening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been been developed new, innovative trial designs that 2) studies that assess the clinical utility of molecular profiling, 3) “master ” protocol trials, iv) can be classified as follows: i) longitudinal cohort studies that implement (or not) “nested ” downstream trials, In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology Reviews polarizing molecular profiling. Emphasis is put on the field of breast cancer clinical trials.