Recent earthquakes in Italy (L'Aquila 2009 and Emilia 2012) highlighted the vulnerability of precast cladding panels, typically associated with a connection system not designed to account for displacement and rotation compatibility between the panels and the supporting structure. Experimental investigations were performed in the past to investigate the in-plane performance of cladding panels and design recommendations have been made accordingly; however, in the case of out-of-plane seismic loads, the load demand is commonly evaluated in the design practice by means of formulations for nonstructural components. This paper summarizes the results obtained from parametric analyses conducted to estimate the out-of-plane load demand in column-to-column cladding panels typical of one-storey commercial and industrial buildings. Empirical equations suitable for both new and existing panels are proposed and compared with the design equations given in Eurocode 8 and ASCE 7. The paper also considers the effects of the development of plastic hinges at the column base and of the roof flexibility on the load demand in panel-to-column connections. The roof flexibility may generate the torsion of the panels; consequently, an analytical procedure to account for such effects is proposed. Finally, general design recommendations are made.