Purpose of Review <p> To review risk factors shared by and unique to nonmedical use of prescription opioids (NUPO) and heroin/illegally manufactured fentanyl (IMF) use, and synthesize them into distinct conceptual pathways.</p> Recent Findings <p> Much discussion of the opioid crisis focuses on a causal “transition” from NUPO to heroin/IMF use. However, most people with NUPO do not go on to use heroin or other illegal opioids; other nonopioid substance use prior to heroin/IMF is ubiquitous; and numerous other risk factors act in concert to facilitate or inhibit heroin/IMF initiation in the context of prior NUPO. Rather than a direct and causal pathway from NUPO to heroin/IMF use, largely overlapping risk factors in biological, environmental, social-interpersonal, and psychological-behavioral domains may give rise to both NUPO and heroin/IMF use in tandem, with some degree of drug-specific influence shaping distinct trajectories.</p> Summary <p> There are genetic and environmental influences shared by and unique to NUPO and heroin/IMF use. NUPO-only use is facilitated by easier access to healthcare and implied legitimacy of POs; negative attitudes toward drug use and lack of drug-involved peers to facilitate access to underground drug markets inhibit heroin/IMF initiation. Heroin/IMF-only use is facilitated by early life adversity, trauma, and social disenfranchisement that increase risk for heroin/IMF use, coupled with limited access to POs (e.g., barriers to healthcare). NUPO+heroin/IMF use is facilitated by strong latent liability for addiction, externalizing psychopathology, and a permissive drug use environment with substance-involved peers, compounded by a flooded drug marketplace. Implications for intervention and policy are discussed.</p>