Recently, there has been considerable interest in developing risk-based sampling for food safety and animal and plant health for efficient allocation of inspection and surveillance resources. The problem of risk-based sampling allocation presents a challenge similar to financial portfolio analysis. Markowitz (1952) laid the foundation for modern portfolio theory based on mean-variance optimization. However, a persistent challenge in implementing portfolio optimization is the problem of estimation error, leading to false “optimal” portfolios and unstable asset weights. In some cases, portfolio diversification based on simple heuristics (e.g., equal allocation) has better out-of-sample performance than complex portfolio optimization methods due to estimation uncertainty. Even for portfolios with a modest number of assets, the estimation window required for true optimization may imply an implausibly long stationary period. The implications for risk-based sampling are illustrated by a simple simulation model of lot inspection for a small, heterogeneous group of producers.