Background: The research proposed herein investigates factors associated with substance use trajectories leading to injection drug use (injection) and the circumstances surrounding injection within two different populations of injection drug users (IDUs). This study aims to identify factors associated with: (1) initiation of substance use through injection, (2) lifetime and current agua celeste use (an inhalant unique to Northern Mexico), and (3) time to initiation of sex work, and initiation of injection. Methods: Three manuscripts form the basis of this dissertation using existing data from two datasets. Manuscript 1 uses data from IDU from the Proyecto El Cuete phase III dataset, and Manuscript 2 and 3 use data from female sex workers who inject drugs (FSW-IDU) in the Mujer Mas Segura dataset. Results: Manuscript 1 identified a sub-group of IDUs who initiated illicit drug use by injecting the drug ('injection first'). 'Injection first' IDUs were more likely to first inject heroin and inject alone, but were not significantly riskier in their current drug use or sexual behaviors compared to IDUs who used illicit drugs prior to injection. Manuscript 2 found that only FSW-IDUs in Ciudad Juarez reported agua celeste use and prevalence overall (53%) and within the past 6 months (47%) was high. Manuscript 3 identified that early abuse and illicit drug use was associated an accelerated time to initiation of both sex work and injection. Low education and a perceived need to enter sex work to support family were associated with a shorter time to sex work initiation, and geographical migration was found to decelerate time to injection initiation. Having an intimate partner suggest sex work and injecting to deal with feelings of depression accelerated time to both sex work and injection initiation when they occurred at the same age. Conclusions: The unique populations of IDUs studied and novel research questions make the findings within this dissertation valuable to the larger field of research on substance use careers. These findings build on previous literature showing that inhalant use is an important risk factor for subsequent injection and may help identify possible avenues for intervention that can delay or prevent onset of initiation of injection drug use and/or sex work.