Honour was embedded in Alessandro Farnese's moral framework and foremost was family honour. His primary duty, of course, was to ensure that the family continued. Following the death of his brother Angelo, the pool of candidates for continuing the family line significantly narrowed: Angelo had one young son, Gabriello, who died in 1496; of two male cousins one, Ranuccio, was killed in battle in 1495 and the other, Pietropaolo, a cleric, died soon after. This left only one other close male relative, Federico, a sickly twelve-year-old second cousin whose life chances in the 1490s were looking poor. Although Farnese's rank of cardinal required celibacy of him, there was no question for him of the duty he was to follow. By 1500 he had formed a relationship with a Roman noble woman, Silvia Ruffini, and together they had four children: Costanza in 1500, Pierluigi in 1503, Paolo in 1504, and Ranuccio in 1509. Cardinal Farnese had Pierluigi and Paolo legitimised by Julius II in 1505 with the Bull of Legitimation specifically referring to the duty of noble males to continue their line.

There is no reliable evidence that Farnese had any mistress other than Silvia. The duration and nature of their relationship is uncertain. Pastor maintains that the cardinal severed the relationship with her in 1513. But that may not be the case. There is no doubt that, consistent with Farnese's fidelity of obligation mentioned earlier, he continued to support her financially until his death.