The emergence of practice-based research networks (PBRN) has facilitated the execution of multifaceted community-based studies. As study complexity increases, so does the number of methodological barriers encountered. This paper’s goal was to delineate methodological barriers and to evaluate the effectiveness of selected strategies and approaches developed and implemented in allowing a prospective, national PBRN cohort study to succeed in enrolling geographically dispersed mother/healthy term infant dyads (n = 4300) on the day of post-partum discharge. Specific methodological barriers included: (1) obtaining multiple Institutional Review Board (IRB) approvals; (2) gathering longitudinal data from multiple individuals; (3) soliciting multiple perspectives on discharge decision making; and (4) bolstering minority enrolment. The most effective strategies and approaches we employed to address these methodological challenges were: (1) preparing and distributing the ‘IRB Packet’; (2) recruiting multiple practices covered by the same IRB; and (3) obtaining supplemental funding for increasing minority enrolment. We expect that other PBRN investigators can benefit from our experience and solutions in the successful conduct of this multifaceted community-based study.