Multijunction (MJ) solar cells are currently seen as the most promising technology toward achieving incomparable solar to electricity conversion efficiency, largely surpassing the best conventional single-junction solar cells. It was recently shown that futuristic cell architectures encompassing increasing number of subcells will likely show increased sensitivity to the spectral distribution of sunlight, giving rise to dramatic variations in the energy output of MJ-based Photovoltaic (PV) systems from one location to the other. Here, we investigate the extent to which MJ cells fine-tuned to the spectral distribution of any particular site are likely to outperform conventionally designed solar cells (tailored to AM1.5 reference solar spectrum). We first tackle the question of the extent to which fine-tuning may improve the performance of MJ cells showing deviations in the values of the main atmospheric parameters, relative to the reference solar spectrum. We then evaluate the potential of fine-tuning in improving the energy output of MJ cell-based PV systems for several locations selected for being representative of the broad diversity of atmospheric and climatic conditions. We demonstrate that the improvement in the energy output one can expect from fine-tuned PV cells strongly depends on how the mean annual spectrum deviates from the reference AM1.5 solar spectrum, with values ranging from ≈0 to more than 30%, depending on the location and the cell architecture considered. Implications for future generations of MJ solar cells are finally discussed.