Mismatching operating conditions negatively affect the extracted energy in photovoltaic (PV) systems. They may also lead to dangerous localized heating phenomena (hot spots) that can cause, in turn, accelerated ageing and reduced reliability. Since the adoption of bypass diodes or smart active switches does not prevent the occurrence of hotspots, it is necessary to investigate alternative strategies. A promising solution is represented by the proper regulation of the operating point of the PV cells in the current vs. voltage (I-V) or power vs. voltage (P-V) planes when mismatching conditions occur. In particular, in this paper, the existence of operating points allowing a suitable compromise between maximization of the extracted power and minimization of thermal stresses, due to hot spots, is experimentally evidenced. Experimental results highlighting the link existing between the operating point in the I-V plane and the PV cell temperature distribution under uniform and mismatching operating conditions are presented and discussed. On the basis of the obtained experimental results, it is possible to state that, when mismatching conditions occur, it is mandatory to properly choose the operating point: the global maximum power point may not be the best operating point. Hence, it is crucial to gain information about the eventual occurrence of mismatching conditions in order to be able to properly choose the best operating point. Therefore, another crucial aspect that is evidenced in this paper is represented by the fact that the detection of the occurrence of mismatching conditions, based on the analysis of the shape of the I-V and/or P-V characteristics, is effective only if the analysis is carried out for both positive and negative voltages.