This chapter addresses a pivotal question at the core of digital transformation in healthcare: why do numerous promising innovations fail to scale or maintain their impact? Despite substantial evidence supporting the benefits of Digital Medicine, real-world adoption is frequently hindered by a complex web of financial, cultural, regulatory, and infrastructural barriers. The chapter begins by framing these barriers not as isolated technical issues but as systemic challenges that necessitate multi-stakeholder solutions. From clinician skepticism and lapses in patient literacy to ambiguity in reimbursement and threats to cybersecurity, each obstacle is examined through a practical and interdisciplinary lens. Financial and resource constraints remain among the most pervasive challenges. The costs associated with implementation—ranging from devices to staff training—often conflict with outdated reimbursement models. The chapter proposes phased rollouts, pilot validation, and value-based care contracts as strategies to mitigate investment risks and demonstrate return on investment (ROI). Collaborating with payers and technology providers can additionally bridge resource gaps. Cultural and organizational resistance is framed as a human challenge rather than a technical one. Digital transformation alters workflows and power dynamics, which can incite fear or disengagement. Strategies such as co-design with clinicians, peer mentorship programs, and transparent communication are critical for fostering trust and acceptance. Digital champions—internal advocates for technology—can serve as catalysts for change. Data privacy and cybersecurity are positioned as facilitators of trust. The chapter delineates how overlapping frameworks, such as GDPR and HIPAA, necessitate rigorous compliance, and how proactive strategies—such as encryption, role-based access, and incident response plans—can mitigate risks while preserving confidence. Real-world examples illustrate how breaches can undermine trust and how swift, transparent actions can contribute to its restoration. The digital divide is reconceptualized as a structural determinant of health equity. Beyond access to devices and connectivity, this chapter addresses usability, health literacy, and cultural relevance. It explores innovative interventions, such as loaner device programs and offline-enabled applications, demonstrating how these initiatives can extend the benefits of digital care to underserved communities. Enhancements to usability—such as multilingual applications and simplified interfaces—are also emphasized as essential enablers of inclusion. Reimbursement and legal ambiguity are identified as policy-level inhibitors of scaling. The chapter presents international examples—such as Germany’s DiGA framework and the Estonia-Finland cross-border e-prescription model—to illustrate how regulatory clarity and payer alignment can expedite adoption. It recommends that countries modernize billing codes, promote reciprocal licensing agreements, and integrate digital therapeutics into benefits packages. A strong emphasis is placed on digital literacy and trust. From structured clinician training to patient engagement through gamification and transparent data practices, the chapter proposes a multi-faceted approach to building competence and confidence. It advocates for the integration of Digital Health curricula in medical education, workload adjustments to facilitate adoption, and continuous feedback loops with end users. The chapter concludes with ten real-world case studies and five practical exercises that address topics such as phased remote monitoring implementation, privacy compliance, cybersecurity incident management, equitable access through loaner devices, and national policy models for reimbursement. These examples ground theory in practice and provide readers with opportunities to internalize key strategies through simulation and reflection. In essence, this chapter reframes barriers to adoption as design opportunities. By anticipating resistance, investing in inclusivity, modernizing policies, and cultivating digital trust, healthcare systems can transition from experimentation to transformation. This chapter equips leaders with the strategic tools, operational models, and cultural insights necessary for constructing Digital Medicine ecosystems that are resilient, scalable, and equitable.