Pt-alloy (Pt-M) nanoparticles (NPs) with less expensive 3d transition metals (M = Ni, Cu, Co) supported on high surface area carbon supports, are currently the state-of-the-art (SoA) solution to reach the production phase in proton exchange membrane fuel cells (PEMFCs). However, while Pt-M electrocatalysts show promise in terms of increased activity for oxygen reduction reaction (ORR) and thus, cost reductions from a significantly lower use of expensive and rare Pt, key challenges in terms of synthesis, activation and stability remain to unlock their true potential. This work systematically tackles them with a combination of electrocatalyst synthesis and characterization methodologies including thin-film rotating disc electrodes (TF-RDE), an electrochemical flow cell linked to an inductively coupled plasma mass spectrometer (EFC-ICP-MS) and testing in 50 cm2 membrane electrode assemblies (MEAs). In the first part of the present work, we highlight the crucial importance of the chemical activation (de-alloying) step on the performance of Pt-M electrocatalysts in the MEA at high current densities (HCDs). In addition, we provide the scientific community a preliminary and facile method of distinguishing between a ‘poorly’ or ‘adequately’ de-alloyed (activated) Pt-alloy electrocatalyst using a much simpler and affordable TF-RDE methodology using the well-known CO-stripping. Since the transition metal cations can also be introduced in a PEMFC due to the degradation of the Pt-M NPs, the second part of the work focuses on presenting clear evidence on the direct impact of the lower voltage limit (LVL) on the stability of Pt-M electrocatalysts. The data suggests that in addition to intrinsic improvements in stability, significant improvements in the PEMFC lifetime can also be obtained via correct MEA design and applied limits of operation, namely restricting not just upper but equally important also lower operation voltage.