Molecular electronics research is a very active area in the field of nanotechnology. It is now well established that individual or self-assembled molecules can behave as nanoscopic switches in transistor and diode configurations. Molecular wires inserted into nanopores and contacted by two metallic electrodes can also be used as active elements for the fabrication of resonant tunneling diodes (RTDs). The RTD current/voltage (I/V) characteristics can display a negative differential resistance (NDR) behavior (i.e., a negative slope in the I/V curve) for reasons that are not yet fully understood. Here we describe a possible mechanism at the quantum-chemical level that is based on conformational effects and accounts for the experimental observation of strong NDR signatures in substituted phenylene ethynylene oligomers. The occurrence of a peak current in the I/V curves is rationalized by analyzing the evolution of the one-electron structure of the molecular wires upon application of a static electric field aligned along the molecular axis (the field simulates the driving voltage applied between the two electrodes in the RTD devices). The results of our calculations provide a general basis to develop strategies for the design of molecular wires displaying an NDR behavior.