To describe vulnerabilities and resources in career development, it is important to consider a life-span and life-long perspective, the different layers of a person’s self, and the interaction between the person and the surrounding environment. To this end, macro- (i.e., public policies, labor market transformations), meso- (i.e., family structure, organizations), and micro-level (i.e., personal factors) determinants have to be considered. The impact of these different levels in our contemporary word leads to a destandardization of career paths and to an increase in the number and complexity of career transitions posing a challenge to people because of the associated risk of marginalization, especially for disadvantaged and vulnerable populations. To understand the dynamics of career development and related adjustment processes, it is important to consider the interplay between work-related vulnerabilities and employees’ adjustment resources. Several contextual resources, such as peer support, or personal resources, such as adaptability, are known to promote work-related and general well-being. This carries important implications for policy-making, promoting life-long learning and guidance, decent and sustainable work, and social inclusion. Moreover, it informs various interventions, in particular those aimed at increasing access to life-long guidance for all.