The present chapter introduces the logical approach adopted in this study and aimed at verifying if, on average, rural areas have a higher probability of self-employment compared with urban areas. Changes over time reflect a broader trend toward self-employment more focused on innovative activities; Covid-19 pandemic confirmed such trends. In some countries, the connection with the public sector played a fundamental role in supporting self-employed workers, especially during recessions. Another crucial aspect that emerged from the analysis is the impact of digitalization and remote work. To address the issue of reverse causality, we used Instrumental Variables (IV) regressions. This method allowed us to isolate the causal effect of rurality on self-employment, using work-related health problems as the instrument. Work-related health issues arising from physically demanding jobs, often present in rural areas, proved to be a good predictor of residence in these areas, especially in countries with significant agricultural (or industrial) sectors.