A medical system comprises a plurality of electrodes; at least one sensor configured to output at least one signal based on at least one physiological parameter of a patient; and a processor. The processor is configured to control delivery of stimulation to the patient using a plurality of electrode configurations. Each of the electrode configurations comprises at least one of the plurality of electrodes. For each of the electrode configurations, the processor is configured to determine a first response of target tissue to the stimulation based on the signals, and a second response of non-target tissue to the stimulation based on the signals. The processor is also configured to select at least one of the electrode configurations for delivery of stimulation to the patient based on the first and second responses for the electrode configurations. As examples, the target tissue may be a left ventricle or vagus nerve.