In the setting of acute coronary syndrome (ACS) the enhancement of analytical performances for several biomarkers improved the understanding of complex ACS pathogenesis highlighting the potential targets of treatment. The introduction of multiplex arrays, developed on ELISA methodology, measuring simultaneously multiple proteins in one assay, allowed the chance to obtain patient multimarker profiles. Aim of this commentary is to clarify the clinical reliability and usefulness of multiplex arrays, in ACS context, referring to available recent methodological and translational research literature. We reported that a certain number of clinical studies in ACS considered these methods but provided poor evidence, since their lack of standardization. The main drawback of multiplex arrays lies in the cross-reactions between the array antibodies with the reagents of co-detected analytes and with the sample matrix proteins. This cross-reactivity rises as the increasing number of markers assayed in the same plate. We have shown that these multiplex arrays were employed to screen markers potentially involved in the disease, among a wide spectrum of proteins, without a preliminary robust biological hypothesis. The need of up-to-date biostatistical approaches is stressed. Researchers should address their efforts to build up and standardize sub-microarrays measuring a lower number of markers than multiplex one, selected on a clear link with ACS evolution.