Transparent PV (TPV) layers allow solar energy exploitation across the thermal, daylighting, and energy conversion domains. However, the current power conversion efficiency (PCE) and visible transmittance (VT) features of such systems may hinder the effectiveness of such solutions when the global performance of the building envelope is considered. In this study we assessed, from a multi-domain perspective, if the performance of façade configurations based on commercially available TPV layers can compete with the performance of façade configurations based on more conventional (opaque) PV solutions. The outcome of this research is thus, on the one hand, a better, evidence-based understanding of the current performance levels of this technology – whether it is mature enough for successful uptake, and which applications are the most relevant – and on the other hand, evidence-based recommendations for product development paths to make TPV systems more competitive for a wider range of applications. In this simulation study we employed a simple room with standardised user patterns and requirements, and repeated the analysis in multiple European climates, to make our results as generic as possible. We carried out the analysis by computing and comparing the performance across the three different domains (total energy use, daylighting, and energy conversion), thanks to a co-simulation environment, of south-facing façade configurations with different TPV or opaque BIPV solutions, which were parametrically changed in terms of window-to-wall ratio, glazing type, and BIPV system. The results showed that TPV systems provided global performance levels that were, in a large range of cases, worse than those of other façade configurations integrating only opaque PV layers and conventional glazing. The trade-off between solar/visual transmittance and absorptance, necessary to ensure a certain PV conversion output in TPV layers, led to a worse global (multi-domain) performance in all the investigated climates. When a fully glazed façade is an absolute design requirement, TPV-based façades can give a better total energy performance than solutions without any PV conversion feature, while providing acceptable daylighting exploitation. However, these envelope solutions showed a worse performance compared to other configurations with a better, more balanced window-to-wall ratio, with BIPV only on opaque surfaces. Accordingly, these findings have implications for both recommended applications of today’s TPV systems and technology development directions. Current TPV systems may be suitable for large, glazed surfaces (such as atria or roofs above circulation spaces) where visual performance requirements are less tight than in office or dwelling settings. TPV solutions can become more competitive for broader façade applications if a PCE of at least 3 times the current value is achieved without reducing the VT. Increasing the VT while keeping the current PCE could also be a suitable research trajectory to enable TPV systems that provide a better balance in solar energy exploitation. Combining a TPV with more advanced glazing solutions (e.g., vacuum insulation or thin-glass glazing) can, however, only marginally expand the range of usability of these systems.